Seiji Nishino
Professor (Research) of Psychiatry & Behavioral Sciences, Emeritus
Psychiatry and Behavioral Sciences - Sleep Medicine
Current Research and Scholarly Interests
The research focus of the Sleep and Circadian Neurobiology (SCN) Laboratory is the study of the sleep and circadian physiology using various animal models. A portion of the research is carried out using rodent models of narcolepsy and circadian rhythm sleep disorders. The laboratory also carries out pharmacological studies aiming to develop new treatments for these sleep disorders.
2023-24 Courses
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Independent Studies (5)
- Directed Reading in Psychiatry
PSYC 299 (Aut, Sum) - Graduate Research
PSYC 399 (Aut, Sum) - Medical Scholars Research
PSYC 370 (Aut, Sum) - Teaching in Psychiatry
PSYC 290 (Aut, Sum) - Undergraduate Research, Independent Study, or Directed Reading
PSYC 199 (Aut, Sum)
- Directed Reading in Psychiatry
All Publications
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Antisense oligonucleotide therapeutic approach for Timothy syndrome.
Nature
2024; 628 (8009): 818-825
Abstract
Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2-6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.
View details for DOI 10.1038/s41586-024-07310-6
View details for PubMedID 38658687
View details for PubMedCentralID 1149428
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Evaluation of the benefits of neutral bicarbonate ionized water baths in an open-label, randomized, crossover trial.
Scientific reports
2024; 14 (1): 1261
Abstract
We previously demonstrated that neutral bicarbonate ionized water (NBIW) bathing enhances blood flow by bicarbonate ions and described the underlying mechanism. However, additional clinical investigation was warranted to investigate the efficacy of NBIW bathing. Hence, we performed a randomized, open-label, crossover trial to examine the effects of NBIW bathing on mental stress, sleep, and immune function. Participants who regularly felt stressed were randomly assigned to NBIW or regular bathing for 4weeks. Mental stress was assessed with the Brief Job Stress Questionnaire (BJSQ) and the Profile of Mood States Second Edition; sleep quality, with the Pittsburgh Sleep Quality Index Japanese version (PSQI-J) and actigraphy; and immune function, with laboratory tests. PSQI-J scores and actigraphy sleep latency and bed out latency improved significantly more with NBIW bathing than with regular bathing (p<0.05). Furthermore, NBIW bathing reduced both stress-induced fluctuations in CD4+ and CD8+ T cell counts and fluctuations in the naive to memory T cell ratio and neutrophil phagocytosis, indicating improved immune function. These findings suggest that daily NBIW bathing could improve mental stress, sleep quality, and immune function and bring about positive health effects in those who experience stress in their daily lives.
View details for DOI 10.1038/s41598-024-51851-9
View details for PubMedID 38218992
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Eurycoma longifolia (Tongkat Ali) enhances wakefulness during active periods but facilitates sleep during resting periods in C57BL/6 mice.
The European journal of neuroscience
2023
Abstract
The effects of the Eurycoma longifolia (also known as Tongkat Ali [TA]) on sleep and wakefulness was evaluated in C57BL/6 mice. While TA has been used as an aphrodisiac in males, it exhibits various pharmacological effects. The most notable effect observed with TA was wake-enhancement during the second half of the active period, accompanied by significant elevations in core body temperature (CBT). In contrast, sleep was enhanced during the resting period (i.e., increase in rapid eye movement [REM] sleep and delta electroencephalography [EEG] power in non-REM sleep) with significant declines in CBT. The transition of TA's effects between resting and active periods was rapid. The results of the experiments in constant darkness indicate that TA prolongs the circadian tau and that this transition is governed by circadian clock mechanisms rather than light exposure. TA did not demonstrate efficacy in aiding sleep in an acute stress-induced insomnia model; thus, TA may be more suitable as a wake-enhancing agent for daytime sleepiness, as sleep propensity tends to accumulate towards the end of active period. Since TA amplifies the rest-activity pattern, prolongs circadian tau and increases REM sleep, thereby reversing some common symptoms seen in elderly subjects, it may also hold promise as a rejuvenating medicine.
View details for DOI 10.1111/ejn.16186
View details for PubMedID 37968729
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BMAL1 loss in oligodendroglia contributes to abnormal myelination and sleep.
Neuron
2023
Abstract
Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology, and BMAL1 are time-of-day dependent. Knockout of Bmal1 in mouse OPCs during development disrupts the expression of genes associated with circadian rhythms, proliferation, density, morphology, and migration, leading to changes in OPC dynamics in a spatiotemporal manner. Furthermore, these deficits translate into thinner myelin, dysregulated cognitive and motor functions, and sleep fragmentation. OPC-specific Bmal1 loss in adulthood does not alter OPC density at baseline but impairs the remyelination of a demyelinated lesion driven by changes in OPC morphology and migration. Lastly, we show that sleep fragmentation is associated with increased prevalence of the demyelinating disorder multiple sclerosis (MS), suggesting a link between MS and sleep that requires further investigation. These findings have broad mechanistic and therapeutic implications for brain disorders that include both myelin and sleep phenotypes.
View details for DOI 10.1016/j.neuron.2023.08.002
View details for PubMedID 37657440
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Analysis of the Effects of Known Sleep-Support Supplements in Relation to Life Habits, Sleep Conditions, and Sleep Problems.
Nutrients
2023; 15 (10)
Abstract
Sleep is a crucial component of health, and insomnia is among the most common and vexing of life-habit-related disorders. While dietary sleep-support supplements can improve sleep, choosing an effective dietary supplement can be challenging for users due to the wide variety of options available and the varying effects experienced by different individuals. In this study, to identify new criteria for estimating the effects of dietary supplements, we examined the relationships among the dietary supplements, the pre-conditions (PCs; defined as the life habits and sleep conditions before supplementation), and the sleep problems of subjects before supplementation. An open, randomized, cross-over intervention trial enrolling 160 subjects was conducted to test the efficacy of each dietary supplement (Analysis 1) and the relationships among dietary supplements, the PCs, and sleep problems (Analysis 2). To this end, l-theanine (200 mg/day), gamma-aminobutyric acid (GABA) (111.1 mg/day), Apocynum venetum leaf extract (AVLE) (50 mg/day), and l-serine (300 mg/day) were administered to subjects. Before the first intervention period, life habits and sleep conditions were surveyed to identify each subject's PCs. For each combination of supplements and sleep problems, PCs were compared between subjects whose sleep problems were improved and subjects whose sleep problems were not improved via supplementation. All the tested supplements were found to ameliorate sleep problems significantly (Analysis 1). In Analysis 2, the PCs specific to improved subjects were found to differ depending on the dietary supplements and sleep problems. In addition, subjects who consumed dairy products often showed improvement in their sleep problems with all the tested supplements. This study suggests the possibility of personalizing sleep-support supplementation based on personal life habits, sleep conditions, and sleep problems, in addition to the known efficacy of dietary supplements.
View details for DOI 10.3390/nu15102377
View details for PubMedID 37242260
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PARTIAL BLUE LIGHT BLOCKING GLASSES ADVANCED SLEEP PHASE BUT DID NOT ALTER SALIVARY MELATONIN SECRETION IN JAPANESE SCHOOLCHILDREN
OXFORD UNIV PRESS INC. 2023: A138
View details for Web of Science ID 001008232900311
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Changes in sleep profile on exposure to sodium chloride and artificially carbonated springs: a pilot study.
Journal of physical therapy science
2023; 35 (5): 330-339
Abstract
[Purpose] Herein, we aimed to investigate the effects of bathing in a sodium chloride spring and an artificially carbonated spring on core body temperature and electroencephalograms, to assess whether the springs facilitate sleep. [Participants and Methods] This randomized, controlled, crossover study evaluated the effects of a sodium chloride spring, an artificially carbonated spring, a plain hot bath, and no bath on sleep. The subjective evaluations and recording of temperature were performed before/after bathing at 40 °C for 15 min at 22:00 h, before nocturnal sleep (0:00-7:00 h), and after the participants (n=8) woke up in the morning. [Results] Bathing significantly increased the core body temperature, with significant subsequent declines observed until bedtime. Participants in the sodium chloride spring group had the highest average core body temperature, while participants in the no-bath group had the lowest average core body temperature before bedtime (23:00-0:00 h). During bedtime (1:00-2:00 h), the participants in the no bath group had the highest average core body temperature, while participants in the artificially carbonated spring group had the lowest average core body temperature. The amount of delta power/min in the first sleep cycle significantly increased in the bathing groups, with the highest value during bedtime being recorded in the artificially carbonated spring group, followed by the sodium chloride spring, plain hot bath, and no-bath groups. These sleep changes were associated with significant declines in the elevated core body temperature. Increased heat dissipation and decreased core body temperature were observed in the artificially carbonated spring and sodium chloride spring groups, which increased the delta power during the first sleep cycle compared with that observed in the plain hot bath group, followed by the no-bath group. [Conclusion] An artificially carbonated spring would be the most appropriate given each circumstance because it did not cause fatigue, as observed with the sodium chloride spring.
View details for DOI 10.1589/jpts.35.330
View details for PubMedID 37131353
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Characteristics of hypersomnia due to inflammatory demyelinating diseases of the central nervous system.
BMJ neurology open
2023; 5 (1): e000428
Abstract
Background: Neuromyelitis optica spectrum disorder (NMOSD) diagnostic criteria for inflammatory demyelinating central nervous system diseases included symptomatic narcolepsy; however, no relevant case-control studies exist. We aimed to examine the relationship among cerebrospinal fluid orexin-A (CSF-OX) levels, cataplexy and diencephalic syndrome; determine risk factors for low-and-intermediate CSF-OX levels (≤200 pg/mL) and quantify hypothalamic intensity using MRI.Methods: This ancillary retrospective case-control study included 50 patients with hypersomnia and 68 controls (among 3000 patients) from Akita University, the University of Tsukuba and community hospitals (200 facilities). Outcomes were CSF-OX level and MRI hypothalamus-to-caudate-nucleus-intensity ratio. Risk factors were age, sex, hypersomnolence and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130%. Logistic regression was performed for the association between the risk factors and CSF-OX levels ≤200 pg/mL.Results: The hypersomnia group (n=50) had significantly more cases of NMOSD (p<0.001), diencephalic syndrome (p=0.006), corticosteroid use (p=0.011), hypothalamic lesions (p<0.023) and early treatment (p<0.001). No cataplexy occurred. In the hypersomnia group, the median CSF-OX level was 160.5 (IQR 108.4-236.5) pg/mL and median MRI hypothalamus-to-caudate-nucleus-intensity ratio was 127.6% (IQR 115.3-149.1). Significant risk factors were hypersomnolence (adjusted OR (AOR) 6.95; 95% CI 2.64 to 18.29; p<0.001) and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% (AOR 6.33; 95% CI 1.18 to 34.09; p=0.032). The latter was less sensitive in predicting CSF-OX levels ≤200 pg/mL. Cases with MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% had a higher rate of diencephalic syndrome (p<0.001, V=0.59).Conclusions: Considering orexin as reflected by CSF-OX levels and MRI hypothalamus-to-caudate-nucleus-intensity ratio may help diagnose hypersomnia with diencephalic syndrome.
View details for DOI 10.1136/bmjno-2023-000428
View details for PubMedID 37396796
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Comparison of Solriamfetol and Modafinil on Arousal and Anxiety-Related Behaviors in Narcoleptic Mice.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
2022
Abstract
Wake-promoting agents are used for the management of excessive daytime sleepiness caused by narcolepsy. Clinical and preclinical data suggests that solriamfetol, a novel dopamine and norepinephrine reuptake inhibitor, is a promising therapeutic option for excessive daytime sleepiness. We provide the first head-to-head comparison of in vivo efficacy between modafinil and solriamfetol in narcoleptic mice. Both compounds induced potent wake-promoting effects in littermate wild-type and orexin-tTA; TetO-DTA mice when dosed at active and resting phases. However, neither modafinil nor solriamfetol alleviated cataplexy. Remarkably, modafinil significantly induced locomotor activity but solriamfetol had small effects. Awake electroencephalogram profiles revealed that modafinil augmented theta oscillation in a dose-dependent manner, but, on the contrary, the response to solriamfetol was blunted, reflecting the differences in their neurochemical properties and anxiogenic effects. Drug-induced anxiety-related behaviors were evaluated at equipotent wake-promoting doses in WT and DTA mice using the elevated plus maze and forced swim tests. Importantly, 100mg/kg of modafinil significantly produced anxiety-related behaviors in WT mice, whereas 150mg/kg of solriamfetol did not have anxiogenic effects. On the other hand, DTA mice exhibited trait anxiety and altered drug responses. Our results suggest that solriamfetol potently promotes wakefulness without psychomotor effects and without inducing anxiety-related behaviors.
View details for DOI 10.1007/s13311-022-01328-2
View details for PubMedID 36544071
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Influences of sleep and lifestyle factors on the risk for covid-19 infections, from internet survey of 10,000 Japanese business workers.
Scientific reports
2022; 12 (1): 19640
Abstract
We conducted an internet survey to assess sociodemographic variables, lifestyle factors, sleep problems, and comorbidities for sleep apnea syndrome (SAS) in COVID-19 and influenza (FLU) infections. Data from 10,323 workers (50.0% male) were analyzed. COVID-19 was diagnosed in 144 subjects (COVID-19+), and 8,693 were classified as not suspected to be infected (COVID-19-). SAS had been diagnosed in 35.4% of the COVID-19+ subjects, but only 231 (2.7%) of the 8,693 COVID-19- subjects. COVID-19+ subjects were more susceptible to FLU (35.4%) compared to COVID-19- subjects (3.0%). A multivariate analysis revealed that higher risks of COVID-19+ were linked to the following factors: going out without a face mask (OR 7.05, 95% CI 4.53-11.00), FLU+ (OR 6.33, 95% CI 3.80-10.54), excessive exercise before going to sleep (OR 2.10, 95% CI 1.63-2.70), SAS+ (OR 5.08, 95% CI 2.88-8.94), younger age (OR 1.05, 95% CI 1.03-1.07), falling sleep while sitting or talking with someone (OR 3.70, 95% CI 2.30-5.95), and use of hypnotics (OR 2.28, 95% CI 1.20-4.30). Since sleep impairment played a relatively small role in COVID-19+/SAS- subjects, we assume that SAS itself was a more significant risk factor for COVID-19 infection rather than sleep impairment. A better understanding of the mechanisms that result in increased susceptibility to COVID-19 in SAS is vital for helping prevent COVID-19.
View details for DOI 10.1038/s41598-022-22105-3
View details for PubMedID 36385119
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Social stress alters sleep in FGF21-deficient mice.
Brain research bulletin
2022
Abstract
Although several previous studies have suggested a relationship between sleep and the stress response, the mechanism underlying this relationship remains largely unknown. Here, we show that fibroblast growth factor 21 (FGF21), a lipid metabolism-related hormone, may play a role in this relationship. In this study, we examined differences in the stress response between FGF21 knockout (KO) mice and wild-type (WT) mice after social defeat stress (SDS). When the amount of non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep and wakefulness were averaged over the dark period after SDS, only KO mice showed significant differences in NREM sleep and wakefulness. In the social interaction test, KO mice seemed to be more prone to social avoidance. Our real-time (RT) -PCR results revealed that the mRNA expression of the stress- and sleep-related gene gamma-aminobutyric acid A receptor subunit alpha 2 was significantly lower in WT mice than in KO mice. Moreover, KO mice showed lower plasma levels of ketone bodies, which also affect sleep/wake regulation, than WT mice. These results suggested that FGF21 might influence sleep/wake regulation by inducing production of an anti-stress agent and/or ketone bodies, which may result in resilience to social stress.
View details for DOI 10.1016/j.brainresbull.2022.10.005
View details for PubMedID 36243208
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Maturation and circuit integration of transplanted human cortical organoids.
Nature
2022; 610 (7931): 319-326
Abstract
Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1-5. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.
View details for DOI 10.1038/s41586-022-05277-w
View details for PubMedID 36224417
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Pharmacologic Management of Excessive Daytime Sleepiness.
Sleep medicine clinics
2022; 17 (3): 485-503
Abstract
Excessive daytime sleepiness (EDS) is defined as "irresistible sleepiness in a situation when an individual would be expected to be awake, and alert." EDS has been a big concern not only from a medical but also from a public health point of view. Patients with EDS have the possibility of falling asleep even when they should wake up and concentrate, for example, when they drive, play sports, or walk outside. In this article, clinical characteristics of common hypersomnia and pharmacologic treatments of each hypersomnia are described.
View details for DOI 10.1016/j.jsmc.2022.06.012
View details for PubMedID 36150809
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Residual effects of low dose of suvorexant, zolpidem, and ramelteon in healthy elderly subjects: A randomized double-blind study.
Neuropsychopharmacology reports
2022
Abstract
INTRODUCTION: Current hypnotic agents have next-day residual effects. The new orexin antagonist, suvorexant, has little muscle relaxation effect on the physical and cognitive function in the following morning and daytime. In this study, the effects of suvorexant, zolpidem, ramelteon and placebo in elderly subjects were evaluated.METHODS: Six men and eight women aged 63-75years received a single tablet and lights were then turned off. Subjects were instructed to sleep from 23:00-6:00 with an interruption from 4:00-4:30 for evaluations. Suvorexant 10 mg, zolpidem 5 mg, ramelteon 4 mg or placebo was administered single time in a randomized, double-blind and crossover design with a one-week drug holiday in between each drug. Measures of objective parameters and subjective ratings were obtained every 2h from 4:00 to 16:00.RESULT: No subjects showed serious side effects from physical observations and vital sign checks before and after hypnotics were taken. During the first sleep period, the REM sleep time with suvorexant was especially longer than that with zolpidem. During the second sleep period, suvorexant had shorter sleep latency and longer stage2 sleep time than ramelteon and zolpidem, respectively. During the whole entire sleep, the REM sleep time with suvorexant was longer than zolpidem and placebo. For the body sway test with closed eye, the main effects of the medicines and zolpidem were significantly better than suvorexant and ramelteon.CONCLUSION: The changes of physical and cognitive functions in healthy elderly after taking hypnotics were not remarkable. Therefore, these three hypnotics maybe appropriate for the elderly people with insomnia for single-time low dose administration.
View details for DOI 10.1002/npr2.12262
View details for PubMedID 35748642
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Brain Mast Cells in Sleep and Behavioral Regulation.
Current topics in behavioral neurosciences
2022
Abstract
The function of mast cells in the brain for the mediation of neurobehavior is largely unknown. Mast cells are a heterogeneous population of granulocytic cells in the immune system. Mast cells contain numerous mediators, such as histamine, serotonin, cytokines, chemokines, and lipid-derived factors. Mast cells localize not only in the periphery but are also resident in the brain of mammalians. Mast cells in the brain are constitutively active, releasing their contents gradually or rapidly by anaphylactic degranulation. Their activity is also increased by a wide range of stimuli including both immune and non-immune signals. Brain mast cell neuromodulation may thus be involved in various neurobehavior in health and diseases.Using Kit mutant mast cell deficient mice (KitW/KitW-v), we obtained results indicating that brain mast cells regulate sleep/wake and other behavioral phenotypes and that histamine from brain mast cells promotes wakefulness. These findings were also confirmed using a newer inducible and Kit-independent mast cell deficient Mas-TRECK (toxin receptor knockout) mouse. Injections of diphtheria toxin (DT) selectively deplete mast cells and reduce wakefulness during the periods of mast cell depletion.We recently introduced a mouse model for chronic sleep loss associated with diabetes. The mice reared on the wire net for 3weeks (i.e., mild stress [MS]) showed decreased amount of non-rapid eye movement (NREM) sleep, increased sleep fragmentation, and abnormal glucose tolerance test [GTT] and insulin tolerance test [ITT], phenotypes which mirror human chronic insomnia. Interestingly, these mice with insomnia showed an increased number of mast cells in both the brain and adipose tissue. Mast cell deficient mice (KitW/KitW-v) and inhibition of mast cell functions with cromolyn or a histamine H1 receptor antagonist administration ameliorated both insomnia and abnormal glycometabolism. Mast cells may therefore represent an important pathophysiological mediator in sleep impairments and abnormal glycometabolism associated with chronic insomnia.
View details for DOI 10.1007/7854_2022_359
View details for PubMedID 35711025
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A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia.
NPJ genomic medicine
2022; 7 (1): 29
Abstract
Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P=2.7*10-8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.
View details for DOI 10.1038/s41525-022-00298-w
View details for PubMedID 35414074
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"Atypical psychoses" and anti-NMDA receptor encephalitis: a review of literature in the mid-twentieth century.
Psychiatry and clinical neurosciences
2021
View details for DOI 10.1111/pcn.13317
View details for PubMedID 34837280
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Sake yeast induces the sleep-promoting effects under the stress-induced acute insomnia in mice.
Scientific reports
2021; 11 (1): 20816
Abstract
Sleep deprivation induces adverse effects on the health, productivity, and performance. The individuals who could not get enough sleep temporarily experience the symptoms of an induced acute insomnia. This study investigated the efficacy of sake yeast in treatment of acute insomnia in mice. The results of this study showed that sake yeast induced a significant dose-dependent wake reduction, a rapid eye movement (REM) and a non-REM (NREM) sleep enhancement during the first 6h after the oral administration of sake yeast with locomotor activity and core body temperature decreases under the stressful environment in a new cage. In fact, the wake amounts at 3h and 6h were significantly reduced after the oral administration of sake yeast compared with the vehicle. The NREM sleep amounts at 3h and 6h significantly increased after the administration of sake yeast compared with the vehicle. The REM amount at 6h significantly increased after the administration of sake yeast compared with the vehicle, but not at 3h. The previous study suggested that the sleep-promoting effects of sake yeast could be referred from the activating effect of adenosine A2A receptor (A2AR). In summary, the sake yeast is an A2AR agonist and may induce sleep due to its stress-reducing and anti-anxiety properties. Further verification of the involvement of adenosine in the pathophysiology of insomnia is needed.
View details for DOI 10.1038/s41598-021-00271-0
View details for PubMedID 34675261
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Altered responses of end-expiratory lung volume and upper airway patency to body posture in diet-induced obese mice.
Physiological reports
2021; 9 (20): e15072
Abstract
OBJECTIVE: Although both obesity and body posture are important factors affecting end-expiratory lung volume (EELV) and upper airway patency, the influence of those factors on EELV and the association between EELV and upper airway calibers are still unknown in mice. This study examined such interaction effects in obese mice to test the hypothesis that obese mice have decreased EELV accompanied by structural alterations of the upper airway.METHODS: A high-resolution in vivo micro-computed tomography was utilized to scan anesthetized lean and diet-induced obese mice in the prone and supine positions, followed by quantifying lung volume and analyzing upper airway morphology.RESULTS: There was a statistically significant interaction between the effects of body weight and posture on both EELV (p=0.0049, eta 2 =0.1041) and upper airway calibers (p=0.0215, eta 2 =0.6304). In lean mice, EELV in the prone position was significantly larger than in the supine position (prone EELV=193.22±9.10l vs. supine EELV=176.01±10.91l; p=0.0072), whereas obese mice did not have such an improvement in EELV in the prone position (prone EELV=174.37±20.23l vs. supine EELV=183.39±17.49l; p=0.0981) and tended to have a smaller upper airway when EELV was low based on Spearman's correlation analysis.CONCLUSIONS: These data indicate that obesity is an important factor compromising both EELV and upper airway calibers in a posture-dependent manner even in mice, which should be taken into consideration in future studies regarding upper airway collapse and lung mechanical properties using mice.
View details for DOI 10.14814/phy2.15072
View details for PubMedID 34676689
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Genetic and demographic predisposing factors associated with pediatric sleepwalking in the Philadelphia Neurodevelopmental Cohort.
Journal of the neurological sciences
2021; 430: 119997
Abstract
OBJECTIVES: Sleepwalking is a parasomnia associated with non-rapid eye movement (NREM) sleep and is formally diagnosed using polysomnography (PSG). However, PSG are difficult to perform on children or adolescents due to needed compliance. To understand this condition in youth, few studies have been conducted on a large cohort of youths with a diverse distribution of ages and races to characterize it better in the absence of PSG. The present study aimed to evaluate the prevalence of sleepwalking in youth, as well as associated demographic and genetic characteristics, using questionnaires in a large pediatric cohort.METHODS: Data from the Philadelphia Neurodevelopmental Cohort (PNC) of 7515 youths aged between 8 and 22years were used in analyses. Demographic and clinical data, including age, sex, and race, and genetic data from 2753 African American (AA) and 4762 European American (EA) subjects were investigated. The age-wise prevalence of sleepwalking in AA and EA subjects was evaluated. Finally, race-specific genome-wide association (GWAS) analyses of sleepwalking were also performed (N=155 AA cases and 2598 AA controls; N=512 EA cases and 4250 EA controls).RESULTS: Lifetime history of sleepwalking correlated with male sex and EA race. A genetic risk locus that reached genome-wide significance was detected at rs73450744 on chromosome 18 in AA, but not EA youth.CONCLUSION: The present results suggest that male sex, EA race, and genetic factors may be associated with higher rates of sleepwalking among youth. Future studies should consider these variables to advance understanding of the complex pathogenesis of sleepwalking.
View details for DOI 10.1016/j.jns.2021.119997
View details for PubMedID 34563919
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Advances in the pharmacological management of non-24-h sleep-wake disorder.
Expert opinion on pharmacotherapy
2021: 1–11
Abstract
Introduction: Melatonin, a hormone that regulates circadian rhythms and the sleep-wake cycle, is produced mainly during the dark period in the pineal gland and is suppressed by light exposure. Patients with non-24-h sleep-wake disorder (non-24) fail to entrain the master clock with the 24-h light-dark cycle due to the lack of light perception to the suprachiasmatic nucleus typically in totally blind individuals or other organic disorders in sighted individuals, causing a progressive delay in the sleep-wake cycle and periodic insomnia and daytime sleepiness.Areas covered: Herein, the authors review the pharmacological therapies including exogenous melatonin and melatonin receptor agonists for the management of non-24. They introduce a historical report about the effects of melatonin on the phase shift and entrainment for blind individuals with the free-running circadian rhythm.Expert opinion: Orally administered melatonin entrains the endogenous circadian rhythm and improves nighttime sleep and daytime alertness for non-24. Currently, tasimelteon is the only approved medication for non-24 by the US Food and Drug Administration and the European Medicines Agency. Treatments that focus only on sleep problems are insufficient for the treatment of non-24, and aids to entrain the free-running rhythm with the light-dark cycle are needed.
View details for DOI 10.1080/14656566.2021.1876665
View details for PubMedID 33618599
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Intracranial mast cells contribute to the control of social behavior in male mice.
Behavioural brain research
2021: 113143
Abstract
Mast cells (MCs) exist intracranially and have been reported to affect higher brain functions in rodents. However, the role of MCs in the regulation of emotionality and social behavior is unclear. In the present study, using male mice, we examined the relationship between MCs and social behavior and investigated the underlying mechanisms. Wild-type male mice intraventricularly injected with a degranulator of MCs exhibited a marked increase in a three-chamber sociability test. In addition, removal of MCs in Mast cell-specific Toxin Receptor-mediated Conditional cell Knock out (Mas-TRECK) male mice showed reduced social preference levels in a three-chamber sociability test without other behavioral changes, such as anxiety-like and depression-like behavior. Mas-TRECK male mice also had reduced serotonin content and serotonin receptor expression and increased oxytocin receptor expression in the brain. These results suggested that MCs may contribute to the regulation of social behavior in male mice. This effect may be partially mediated by serotonin derived from MCs in the brain.
View details for DOI 10.1016/j.bbr.2021.113143
View details for PubMedID 33516739
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The anticataplectic and REM suppression effect of milnacipran, an SNRI, on human and canine narcolepsy
SLEEP AND BIOLOGICAL RHYTHMS
2021
View details for DOI 10.1007/s41105-020-00298-2
View details for Web of Science ID 000604091500001
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Detailed evaluation of the upper airway in the Dp(16)1Yey mouse model of Down syndrome.
Scientific reports
2020; 10 (1): 21323
Abstract
A high prevalence of obstructive sleep apnea (OSA) has been reported in Down syndrome (DS) owing to the coexistence of multiple predisposing factors related to its genetic abnormality, posing a challenge for the management of OSA. We hypothesized that DS mice recapitulate craniofacial abnormalities and upper airway obstruction of human DS and can serve as an experimental platform for OSA research. This study, thus, aimed to quantitatively characterize the upper airway as well as craniofacial abnormalities in Dp(16)1Yey (Dp16) mice. Dp16 mice demonstrated craniofacial hypoplasia, especially in the ventral part of the skull and the mandible, and rostrally positioned hyoid. These changes were accompanied with a shorter length and smaller cross-sectional area of the upper airway, resulting in a significantly reduced upper airway volume in Dp16 mice. Our non-invasive approach, a combination of computational fluid dynamics and high-resolution micro-CT imaging, revealed a higher negative pressure inside the airway of Dp16 mice compared to wild-type littermates, showing the potential risk of upper airway collapse. Our study indicated that Dp16 mice can be a useful model to examine the pathophysiology of increased upper airway collapsibility of DS and to evaluate the efficacy of therapeutic interventions for breathing and sleep anomalies.
View details for DOI 10.1038/s41598-020-78278-2
View details for PubMedID 33288820
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Evaluations of effects of sleep surfaces on athletic performance in youth.
Scientific reports
2020; 10 (1): 11805
Abstract
We recently demonstrated that sleeping on high rebound [HR] mattress toppers induced a continuous and more rapid decline in core body temperature compared to low rebound [LR] mattress toppers during the initial phase of nocturnal sleep in young healthy volunteers. HR toppers are characterized by their supportive feel and high breathability whereas LR toppers are pressure-absorbing. In the current study, we evaluated effects of HR mattress toppers on objectively-(actigraphy) and subjectively-(questionnaires) evaluated sleep, vigilance (psychomotor vigilance test), and athletic performance (40-m sprint time, long jump distance, and star drill time) in youth male athletes age 10-19, in two sessions: fifty-one subjects in 2013 (study I) and 23 subjects in 2014 (study II). Sleeping on HR mattress toppers for four to six weeks improved some athletic performance measures compared to sleeping on LR or sleeping directly on spring mattresses without a topper. Statistically significant improvements in 40-m sprint time in study I (compared to LR) and in star drill time in study II (no topper) were observed. No changes in sleep and psychomotor vigilance were observed. These results suggest selecting optimal sleep surfaces may contribute to the maximization of athletic performances, and further studies are warranted.
View details for DOI 10.1038/s41598-020-68795-5
View details for PubMedID 32678211
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Pharmacologic Management of Excessive Daytime Sleepiness.
Sleep medicine clinics
2020; 15 (2): 177–94
Abstract
Excessive daytime sleepiness (EDS) is related to medical and social problems, including mental disorders, physical diseases, poor quality of life, and so forth. According to the International Classification of Sleep Disorders, Third Edition, diseases that result from EDS are narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, hypersomnia due to a medical disorder, and others. EDS is usually treated using amphetamine-like central nervous system stimulants or modafinil and its R-enantiomer, armodafinil, wake-promoting compounds unrelated to amphetamines; a variety of new drugs are under development. The side effects of some stimulants are potent and careful selection and management are required.
View details for DOI 10.1016/j.jsmc.2020.02.006
View details for PubMedID 32386693
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Neuronal defects in a human cellular model of 22q11.2 deletion syndrome.
Nature medicine
2020
Abstract
22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.
View details for DOI 10.1038/s41591-020-1043-9
View details for PubMedID 32989314
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Intraperitoneal injection of ginkgolide B, a major active compound of Ginkgo biloba, dose-dependently increases the amount of wake and decreases non-rapid eye movement sleep in C57BL/6 mice.
Neuroscience letters
2020: 134832
Abstract
The terpene lactones of Ginkgo biloba extract, namely ginkgolides (A, B, and C) and bilobalide, possess antioxidant, anti-inflammatory, and neuroprotective effects. They are widely prescribed for the treatment of cerebral dysfunctions and neurological impairments. In addition, they demonstrate antagonistic action at the gamma-aminobutyric acid type A and glycine receptors, which are members of the ligand-gated ion channel superfamily. In the present study, the effects of ginkgolides (A, B, and C) and bilobalide on sleep in C57BL/6 mice were investigated. Ginkgolide B was found to dose-dependently increase the amount of wake and decrease that of non-rapid eye movement sleep without changes in the electroencephalography power density of each sleep/wake stage, core body temperature and locomotor activity for the first 6 h after intraperitoneal injection. Of note, the amount of wake after injection of 5 mg/kg of ginkgolide B showed a significant increase (14.9%) compared with that of vehicle (P = 0.005). In contrast, there were no significant differences in the amount of sleep, core body temperature, and locomotor activity in the mice injected with ginkgolide A and C. Bilobalide briefly induced a decrease in locomotor activity but did not exert significant effects on the amounts of sleep and wake. The modes of action of the wake-enhancing effects of ginkgolide B are unknown. However, it may act through the antagonism of gamma-aminobutyric acid type A and glycine receptors because it is established that these inhibitory amino acids mediate sleep and sleep-related physiology. It is of interest to further evaluate the stimulant and awaking actions of ginkgolide B on the central nervous system in clinical and basic research studies.
View details for DOI 10.1016/j.neulet.2020.134832
View details for PubMedID 32050100
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Tasimelteon for treating non-24-h sleep-wake rhythm disorder
EXPERT OPINION ON PHARMACOTHERAPY
2019
View details for DOI 10.1080/14656566.2019.1603293
View details for Web of Science ID 000466006500001
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Tasimelteon for treating non-24-h sleep-wake rhythm disorder.
Expert opinion on pharmacotherapy
2019: 1–9
Abstract
INTRODUCTION: Non-24-h sleep-wake rhythm disorder (non-24) is observed in approximately half of totally blind individuals, a condition caused by their circadian pacemaker in the suprachiasmatic nucleus not being entrained to 24 h due to a lack of light perceptions. These subjects have a progressively delayed circadian cycle each day, non-24 periodically inducing nighttime insomnia and daytime sleepiness. Tasimelteon is a dual melatonin receptor agonist with high affinity for the melatonin 2 receptor, and it entrains endogenous melatonin rhythms and sleep-wake cycles in individuals with non-24. Areas covered: Herein, the authors review the treatment of non-24 with tasimelteon. The authors further compare tasimelteon with other melatonin receptor agonists. Expert opinion: The treatment strategies for non-24 aim to resynchronize the free-running rhythm with the 24 h light-dark cycle. Tasimelteon entrains circadian rhythms and improves the sleep-wake functions of individuals with non-24. Furthermore, the RESET study demonstrated that 20% of patients that discontinued tasimelteon maintained circadian entrainment whereas 90% of those who continued it maintained circadian entrainment. Long-term administration of tasimelteon is safe and well tolerated, and it is the only pharmacological therapy approved by the US Food and Drug Administration and the European Medicines Agency for non-24.
View details for PubMedID 30990759
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BRAIN RESIDENT MAST CELLS REGULATE BRAIN HISTAMINE CONTENT AND PROMOTE WAKEFULNESS
OXFORD UNIV PRESS INC. 2019
View details for Web of Science ID 000471071000126
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HPLC analysis of CSF hypocretin-1 in type 1 and 2 narcolepsy.
Scientific reports
2019; 9 (1): 477
Abstract
Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin (hcrt) neurons in the hypothalamus. Cerebrospinal fluid (CSF) hcrt-1 measurement has been well established as a gold standard of narcolepsy diagnosis, although some portions of narcoleptic patients show normal hcrt-1 levels. We aimed to examine peptide degradation of hcrt-1 and its abnormality in the CSF of patients by using high performance liquid chromatography (HPLC) followed by radioimmunoassay (RIA). CSF was collected from healthy controls, narcoleptic patients of type 1 with hcrt-1 deficiency, type 1 with normal hcrt-1 level, and type 2 with normal hcrt-1 level. We found that the majority of hcrt-1 immunoreactivity in extracted CSF was derived from unauthentic hcrt-1 peaks, which are predicted to be inactive metabolites, and the intact hcrt-1 peptide was less than 10% of the gross amount, suggesting that the regular RIA for CSF hcrt-1 measures largely reflect the unauthentic hcrt-1-related metabolites rather than the intact one. As expected, all hcrt-1-related peaks were abolished in type 1 with hcrt-1 deficiency. Importantly, we also found that the sum of the authentic hcrt-1 peptide (peaks 3 and 4) significantly decreased in non-deficient type 1 and tended to decrease in type 2 narcoleptic patients although the levels with the regular RIA in non-extracted CSF was equivalent to healthy controls. Immunoreactivity with unauthentic hcrt-1 metabolites may masks the possible decline in authentic hcrt-1 level caused by the partial loss of hcrt neurons. Our findings may provide new insights into the degradation of the hcrt-1 peptide and the pathophysiology of narcolepsy.
View details for PubMedID 30679597
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Measurement of cerebrospinal fluid orexin-A (hypocretin-1) by enzyme-linked immunosorbent assay: A comparison with radioimmunoassay
PSYCHIATRY AND CLINICAL NEUROSCIENCES
2018; 72 (11): 849–50
View details for PubMedID 30159979
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High rebound mattress toppers facilitate core body temperature drop and enhance deep sleep in the initial phase of nocturnal sleep
PLOS ONE
2018; 13 (6): e0197521
Abstract
Recently, several new materials for mattresses have been introduced. Although some of these, such as low rebound (pressure-absorbing/memory foam) and high rebound mattresses have fairly different characteristics, effects of these mattresses on sleep have never been scientifically evaluated. In the current study, we have evaluated effects of a high rebound mattress topper [HR] on sleep and its associated physiology, and the effects were compared to those of a low rebound mattress toppers (LR) in healthy young (n = 10) and old (n = 20) adult males with a randomized, single-blind, cross over design. We found that sleeping with HR compared to LR induced a larger decline in core body temperature (CBT) in the initial phase of nocturnal sleep both in young (minimum CBT: 36.05 vs 36.35°C) and old (minimum CBT: 36.47 vs. 36.55°C) subjects, and declines in the CBT were associated with increases in deep sleep/delta power (+27.8% in young and +24.7% in old subjects between 11:00-01:00). We also found significantly smaller muscle activities during roll over motions with HR (-53.0 to -66.1%, depending on the muscle) during a separate daytime testing. These results suggest that sleeping with HR in comparison to with LR, may facilitate restorative sleep at the initial phase of sleep.
View details for PubMedID 29949584
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An overview of hypocretin based therapy in narcolepsy
EXPERT OPINION ON INVESTIGATIONAL DRUGS
2018; 27 (4): 389–406
Abstract
Narcolepsy with cataplexy is most commonly caused by a loss of hypocretin/orexin peptide-producing neurons in the hypothalamus (i.e., Narcolepsy Type 1). Since hypocretin deficiency is assumed to be the main cause of narcoleptic symptoms, hypocretin replacement will be the most essential treatment for narcolepsy. Unfortunately, this option is still not available clinically. There are many potential approaches to replace hypocretin in the brain for narcolepsy such as intranasal administration of hypocretin peptides, developing small molecule hypocretin receptor agonists, hypocretin neuronal transplantation, transforming hypocretin stem cells into hypothalamic neurons, and hypocretin gene therapy. Together with these options, immunotherapy treatments to prevent hypocretin neuronal death should also be developed. Areas covered: In this review, we overview the pathophysiology of narcolepsy and the current and emerging treatments of narcolepsy especially focusing on hypocretin receptor based treatments. Expert opinion: Among hypocretin replacement strategies, developing non-peptide hypocretin receptor agonists is currently the most encouraging since systemic administration of a newly synthesized, selective hypocretin receptor 2 agonist (YNT-185) has been shown to ameliorate symptoms of narcolepsy in murine models. If this option is effective in humans, hypocretin cell transplants or gene therapy technology may become realistic in the future.
View details for PubMedID 29623725
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Advances in pharmaceutical treatment options for narcolepsy
EXPERT OPINION ON ORPHAN DRUGS
2018; 6 (10): 597–610
View details for DOI 10.1080/21678707.2018.1521267
View details for Web of Science ID 000448064200006
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Low dose of aripiprazole advanced sleep rhythm and reduced nocturnal sleep time in the patients with delayed sleep phase syndrome: an open-labeled clinical observation
NEUROPSYCHIATRIC DISEASE AND TREATMENT
2018; 14: 1281–86
Abstract
Delayed sleep phase syndrome (DSPS) is a chronic dysfunction of circadian rhythm of the subject that impairs functioning in social, occupational, or other spheres. High rate of depression is found among DSPS patients. Aripiprazole (APZ), a second-generation antipsychotic, is effective in treatment of depression as well as schizophrenia. Recently, few case reports show the effectiveness of APZ in treating DSPS and non-24-hour sleep-wake rhythm disorder. Therefore, we tried to treat DSPS with depression using APZ.Twelve subjects (including four women) aged 19-64 years were included. The subjects were prescribed initially 0.5-3 mg of APZ once a day with subsequent dose adjustments.Sleep onset, midpoint of sleep, and sleep offset were significantly advanced by 1.1, 1.8, and 2.5 hours, respectively. Unexpectedly, sleep duration became significantly shorter by 1.3 hours after treatment. Their depressive moods showed an unremarkable change.Low dose of APZ advanced the sleep rhythm and reduced nocturnal sleep time in the subjects with DSPS. Since it is not easy for physicians to treat prolonged sleep duration often associated with DSPS, this medication would become a new therapeutic option for these patients.
View details for PubMedID 29849459
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Mast cell involvement in glucose tolerance impairment caused by chronic mild stress with sleep disturbance
SCIENTIFIC REPORTS
2017; 7: 13640
Abstract
We have developed a chronic mild stress (MS) mouse model by simply rearing mice on a wire net for 3 weeks and investigated the effects of MS on glucose homeostasis and sleep. MS mice showed impaired glucose tolerance and disturbed sleep. One-week treatment with a histamine H1 receptor antagonist (H1RA) ameliorated the glucose intolerance and improved sleep quality in MS mice. MS mice showed an increased number of mast cells in both adipose tissue and the brain. Inhibition of mast cell function ameliorated the impairment in both glucose tolerance and sleep. Together, these findings indicate that mast cells may represent an important pathophysiological mediator in sleep and energy homeostasis.
View details for PubMedID 29057915
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Pharmacologic Management of Excessive Daytime Sleepiness.
Sleep medicine clinics
2017; 12 (3): 461-478
Abstract
Excessive daytime sleepiness (EDS) is related to medical and social problems, including mental disorders, physical diseases, poor quality of life, and so forth. According to the International Classification of Sleep Disorders, Third Edition, diseases that result from EDS are narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, hypersomnia due to a medical disorder, and others. EDS is usually treated using amphetamine-like central nervous system stimulants or modafinil and its R-enantiomer, armodafinil, wake-promoting compounds unrelated to amphetamines; a variety of new drugs are under development. The side effects of some stimulants are potent and careful selection and management are required.
View details for DOI 10.1016/j.jsmc.2017.03.019
View details for PubMedID 28778242
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N-Methyl-D-aspartate receptor antibody could be a cause of catatonic symptoms in psychiatric patients: case reports and methods for detection
NEUROPSYCHIATRIC DISEASE AND TREATMENT
2017; 13: 339-345
Abstract
The symptoms of catatonia have been reported to be similar to the initial symptoms of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Subsequently, this autoimmune limbic encephalitis has been noticed by many psychiatrists. For a differential diagnosis of catatonic state, it is important to detect anti-NMDAR encephalitis. This encephalitis is expected to be in remission by early detection and treatment. We should be more cautious about catatonic symptoms of schizophrenia. When a patient is suspected of having encephalitis, we should screen for anti-NMDAR antibodies in cerebrospinal fluid samples using a cell-based assay. We describe the methods of NMDAR antibody detection and the etiology of this encephalitis with case reports. Two representative cases with catatonia and non-catatonia (brief psychotic disorder) were reported. Schizophrenia is a general, heterogeneous, and complicated disorder, and its pathophysiology is unknown. There is an established evidence of NMDAR hypofunction, which is the functional disconnection of the central component; this is one of the most recognized models for schizophrenia. Furthermore, it is said that autoimmune mechanisms have been involved, at least in subgroups of schizophrenia patients. Further study of anti-NMDAR antibody and its related encephalitis would give essential clues for the research of schizophrenia, catatonia, and atypical psychosis.
View details for DOI 10.2147/NDT.S125800
View details for Web of Science ID 000393495000001
View details for PubMedID 28223808
View details for PubMedCentralID PMC5308574
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Wake-promoting effects of ONO-4127Na, a prostaglandin DP1 receptor antagonist, in hypocretin/orexin deficient narcoleptic mice.
Neuropharmacology
2016; 110: 268-276
Abstract
Prostaglandin (PG)D2 is an endogenous sleep substance, and a series of animal studies reported that PGD2 or PGD2 receptor (DP1) agonists promote sleep, while DP1 antagonists promote wakefulness. This suggests the possibility of use of PG DP1 antagonists as wake-promoting compounds. We therefore evaluated the wake-promoting effects of ONO-4127Na, a DP1 antagonist, in a mouse model of narcolepsy (i.e., orexin/ataxin-3 transgenic mice) and compared those to effects of modafinil. ONO-4127Na perfused in the basal forebrain (BF) area potently promoted wakefulness in both wild type and narcoleptic mice, and the wake-promoting effects of ONO-4127Na at 2.93 × 10(-4) M roughly corresponded to those of modafinil at 100 mg/kg (p.o.). The wake promoting effects of ONO-4127Na was observed both during light and dark periods, and much larger effects were seen during the light period when mice slept most of the time. ONO-4127Na, when perfused in the hypothalamic area, had no effects on sleep. We further demonstrated that wake-promoting effects of ONO-4127Na were abolished in DP1 KO mice, confirming that the wake-promoting effect of ONO-4127Na is mediated by blockade of the PG DP1 receptors located in the BF area. ONO-4127Na reduced DREM, an EEG/EMG assessment of behavioral cataplexy in narcoleptic mice, suggesting that ONO-4127Na is likely to have anticataplectic effects. DP1 antagonists may be a new class of compounds for the treatment of narcolepsy-cataplexy, and further studies are warranted.
View details for DOI 10.1016/j.neuropharm.2016.07.013
View details for PubMedID 27474349
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Decline of CSF orexin (hypocretin) levels in Prader-Willi syndrome.
American journal of medical genetics. Part A
2016; 170A (5): 1181-1186
Abstract
Prader-Willi syndrome is a congenital neurodevelopmental disorder resulting from deletion of the paternal copies of genes within the chromosome region 15q11-q13. Patients with Prader-Willi syndrome often exhibit excessive daytime sleepiness, excessive appetite, and obesity. As is the case in narcolepsy, orexin (hypocretin) may be responsible for these symptoms. However, reports showing cerebrospinal fluid orexin levels in Prader-Willi syndrome patients have been limited. The aim of this study was to examine the relationship between the characteristic symptoms of Prader-Willi syndrome and cerebrospinal fluid orexin levels. We clinically identified 14 Prader-Willi syndrome patients and examined their cerebrospinal fluid orexin levels. A total of 12 patients with a 15q11-q13 deletion and two patients with maternal uniparental disomy of chromosome 15 were identified. A total of 37 narcoleptic patients and 14 idiopathic hypersomnia patients were recruited for comparison. Cerebrospinal fluid orexin levels (median [25-75 percentiles]) in the 14 Prader-Willi syndrome patients were intermediate (192 [161-234.5] pg/ml), higher than in the narcoleptic patients, but lower than in the idiopathic hypersomnia patients. Body mass index of the Prader-Willi syndrome patients was higher than in the narcoleptic and idiopathic hypersomnia patients. There was also a negative correlation between Epworth sleepiness scale scores and orexin levels in Prader-Willi syndrome patients. Decreased cerebrospinal fluid orexin levels in Prader-Willi syndrome may play an important role in severity of obesity and excessive daytime sleepiness. © 2016 Wiley Periodicals, Inc.
View details for DOI 10.1002/ajmg.a.37542
View details for PubMedID 26738920
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Decline of CSF orexin (hypocretin) levels in Prader-Willi syndrome.
American journal of medical genetics. Part A
2016; 170 (5): 1181-1186
View details for DOI 10.1002/ajmg.a.37542
View details for PubMedID 26738920
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A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2016; 113 (11): E1536-E1544
Abstract
In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes.
View details for DOI 10.1073/pnas.1600039113
View details for Web of Science ID 000372014200017
View details for PubMedCentralID PMC4801303
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A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait.
Proceedings of the National Academy of Sciences of the United States of America
2016; 113 (11): E1536-44
Abstract
In humans, the connection between sleep and mood has long been recognized, although direct molecular evidence is lacking. We identified two rare variants in the circadian clock gene PERIOD3 (PER3-P415A/H417R) in humans with familial advanced sleep phase accompanied by higher Beck Depression Inventory and seasonality scores. hPER3-P415A/H417R transgenic mice showed an altered circadian period under constant light and exhibited phase shifts of the sleep-wake cycle in a short light period (photoperiod) paradigm. Molecular characterization revealed that the rare variants destabilized PER3 and failed to stabilize PERIOD1/2 proteins, which play critical roles in circadian timing. Although hPER3-P415A/H417R-Tg mice showed a mild depression-like phenotype, Per3 knockout mice demonstrated consistent depression-like behavior, particularly when studied under a short photoperiod, supporting a possible role for PER3 in mood regulation. These findings suggest that PER3 may be a nexus for sleep and mood regulation while fine-tuning these processes to adapt to seasonal changes.
View details for DOI 10.1073/pnas.1600039113
View details for PubMedID 26903630
View details for PubMedCentralID PMC4801303
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The pathogenesis of narcolepsy, current treatments and prospective therapeutic targets
EXPERT OPINION ON ORPHAN DRUGS
2016; 4 (1): 63-82
View details for DOI 10.1517/21678707.2016.1117973
View details for Web of Science ID 000367400600002
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Basal forebrain circuit for sleep-wake control.
Nature neuroscience
2015; 18 (11): 1641-1647
Abstract
The mammalian basal forebrain (BF) has important roles in controlling sleep and wakefulness, but the underlying neural circuit remains poorly understood. We examined the BF circuit by recording and optogenetically perturbing the activity of four genetically defined cell types across sleep-wake cycles and by comprehensively mapping their synaptic connections. Recordings from channelrhodopsin-2 (ChR2)-tagged neurons revealed that three BF cell types, cholinergic, glutamatergic and parvalbumin-positive (PV+) GABAergic neurons, were more active during wakefulness and rapid eye movement (REM) sleep (wake/REM active) than during non-REM (NREM) sleep, and activation of each cell type rapidly induced wakefulness. By contrast, activation of somatostatin-positive (SOM+) GABAergic neurons promoted NREM sleep, although only some of them were NREM active. Synaptically, the wake-promoting neurons were organized hierarchically by glutamatergic→cholinergic→PV+ neuron excitatory connections, and they all received inhibition from SOM+ neurons. Together, these findings reveal the basic organization of the BF circuit for sleep-wake control.
View details for DOI 10.1038/nn.4143
View details for PubMedID 26457552
View details for PubMedCentralID PMC5776144
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Residual effects of zolpidem, triazolam, rilmazafone and placebo in healthy elderly subjects: a randomized double-blind study.
Sleep medicine
2015; 16 (11): 1395-1402
View details for DOI 10.1016/j.sleep.2015.05.021
View details for PubMedID 26498242
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Relationship of orexin (hypocretin) system and astrocyte activation in Parkinson's disease with hypersomnolence
SLEEP AND BIOLOGICAL RHYTHMS
2015; 13 (3): 252-260
View details for DOI 10.1111/sbr.12112
View details for Web of Science ID 000357325000008
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The Sleep-Promoting and Hypothermic Effects of Glycine are Mediated by NMDA Receptors in the Suprachiasmatic Nucleus
NEUROPSYCHOPHARMACOLOGY
2015; 40 (6): 1405-1416
Abstract
The use of glycine as a therapeutic option for improving sleep quality is a novel and safe approach. However, despite clinical evidence of its efficacy, the details of its mechanism remain poorly understood. In this study, we investigated the site of action and sleep-promoting mechanisms of glycine in rats. In acute sleep disturbance, oral administration of glycine-induced non-rapid eye movement (REM) sleep and shortened NREM sleep latency with a simultaneous decrease in core temperature. Oral and intracerebroventricular injection of glycine elevated cutaneous blood flow (CBF) at the plantar surface in a dose-dependent manner, resulting in heat loss. Pretreatment with N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and CGP78608 but not the glycine receptor antagonist strychnine inhibited the CBF increase caused by glycine injection into the brain. Induction of c-Fos expression was observed in the hypothalamic nuclei, including the medial preoptic area (MPO) and the suprachiasmatic nucleus (SCN) shell after glycine administration. Bilateral microinjection of glycine into the SCN elevated CBF in a dose-dependent manner, whereas no effect was observed when glycine was injected into the MPO and dorsal subparaventricular zone. In addition, microinjection of D-serine into the SCN also increased CBF, whereas these effects were blocked in the presence of L-701324. SCN ablation completely abolished the sleep-promoting and hypothermic effects of glycine. These data suggest that exogenous glycine promotes sleep via peripheral vasodilatation through the activation of NMDA receptors in the SCN shell.
View details for DOI 10.1038/npp.2014.326
View details for Web of Science ID 000352968100011
View details for PubMedID 25533534
View details for PubMedCentralID PMC4397399
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Apnea during Cheyne-Stokes-like breathing detected by a piezoelectric sensor for screening of sleep disordered breathing
SLEEP AND BIOLOGICAL RHYTHMS
2015; 13 (1): 57-67
View details for DOI 10.1111/sbr.12097
View details for Web of Science ID 000347460300007
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Chronic Powder Diet After Weaning Induces Sleep, Behavioral, Neuroanatomical, and Neurophysiological Changes in Mice.
PloS one
2015; 10 (12)
View details for DOI 10.1371/journal.pone.0143909
View details for PubMedID 26630494
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Noninvasive detection of sleep/wake changes and cataplexy-like behaviors in orexin/ataxin-3 transgenic narcoleptic mice across the disease onset
EXPERIMENTAL NEUROLOGY
2014; 261: 744-751
Abstract
Sleep and behavioral monitoring of young mice is necessary for understating the progress of symptoms in congenital and acquired diseases associated with sleep and movement disorders. In the current study, we have developed a non-invasive sleep monitoring system that identifies wake and sleep patterns of newborn mice using a simple piezoelectric transducer (PZT). Using this system, we have succeeded in detecting age-dependent occurrences and changes in sleep fragmentation of orexin/ataxin-3 narcoleptic mice (a narcoleptic mouse model with postnatal hypocretin/orexin cell death) across the disease onset. We also detected REM sleep/cataplexy patterns (i.e., immobility with clear heartbeat [IMHB] signals due to the flaccid posture) by the PZT system, and found that sudden onset of REM sleep-like episodes specifically occur in narcoleptic, but not in wild type mice, suggesting that these episodes are likely cataplexy. In contrast, gradual onset of IMHB likely reflects occurrence of REM sleep. In summary, we have shown that the PZT system is useful as a non-invasive sleep and behavior monitoring system to analyze the developmental aspects of sleep and movement disorders in mice models.
View details for DOI 10.1016/j.expneurol.2014.08.004
View details for Web of Science ID 000343531500080
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Noninvasive detection of sleep/wake changes and cataplexy-like behaviors in orexin/ataxin-3 transgenic narcoleptic mice across the disease onset.
Experimental neurology
2014; 261: 744-751
Abstract
Sleep and behavioral monitoring of young mice is necessary for understating the progress of symptoms in congenital and acquired diseases associated with sleep and movement disorders. In the current study, we have developed a non-invasive sleep monitoring system that identifies wake and sleep patterns of newborn mice using a simple piezoelectric transducer (PZT). Using this system, we have succeeded in detecting age-dependent occurrences and changes in sleep fragmentation of orexin/ataxin-3 narcoleptic mice (a narcoleptic mouse model with postnatal hypocretin/orexin cell death) across the disease onset. We also detected REM sleep/cataplexy patterns (i.e., immobility with clear heartbeat [IMHB] signals due to the flaccid posture) by the PZT system, and found that sudden onset of REM sleep-like episodes specifically occur in narcoleptic, but not in wild type mice, suggesting that these episodes are likely cataplexy. In contrast, gradual onset of IMHB likely reflects occurrence of REM sleep. In summary, we have shown that the PZT system is useful as a non-invasive sleep and behavior monitoring system to analyze the developmental aspects of sleep and movement disorders in mice models.
View details for DOI 10.1016/j.expneurol.2014.08.004
View details for PubMedID 25118620
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Association between heart rate variability, blood pressure and autonomic activity in cyclic alternating pattern during sleep.
Sleep
2014; 37 (1): 187-194
Abstract
Cyclic alternating pattern (CAP) is frequently followed by changes in heart rate (HR) and blood pressure (BP), but the sequential associations between CAP and autonomic nerve activity have not been studied. The study aimed to reveal the precise changes in heart rate variability (HRV) during phase A of the CAP cycle.Polysomnography was recorded according to the CAP Atlas (Terzano, 2002), and BP and electrocardiogram were simultaneously recorded. The complex demodulation method was used for analysis of HRV and evaluation of autonomic nerve activity.Academic sleep laboratory.Ten healthy males.The increase in HR (median [first quartile - third quartile]) for each subtype was as follows: A1, 0.64 (-0.30 to 1.69), A2, 1.44 (0.02 to 3.79), and A3, 6.24 (2.53 to 10.76) bpm (A1 vs. A2 P < 0.001, A1 vs. A3 P < 0.001, A2 vs. A3 P < 0.001). The increase in BP for each subtype was as follows: A1, 1.23 (-2.04 to 5.75), A2, 1.76 (-1.46 to 9.32), and A3, 12.51 (4.75 to 19.94) mm Hg (A1 vs. A2 P = 0.249, A1 vs. A3 P < 0.001, A2 vs. A3 P < 0.001). In all of phase A, the peak values for HR and BP appeared at 4.2 (3.5 to 5.4) and 8.4 (7.0 to 10.3) seconds, respectively, after the onset of phase A. The area under the curve for low-frequency and high-frequency amplitude significantly increased after the onset of CAP phase A (P < 0.001) and was higher in the order of subtype A3, A2, and A1 (P < 0.001).All phase A subtypes were accompanied with increased heart rate variability, and the largest heart rate variability was seen in subtype A3, while a tendency for less heart rate variability was seen in subtype A1.
View details for DOI 10.5665/sleep.3334
View details for PubMedID 24470707
View details for PubMedCentralID PMC3902872
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[Anti-NMDA encephalitis in psychiatry; malignant catatonia, atypical psychosis and ECT].
Rinsho¯ shinkeigaku = Clinical neurology
2014; 54 (12): 1103-1106
Abstract
The symptoms of malignant (lethal) catatonia has been reported similar to initial symptoms of anti-NMDAR encephalitis. Subsequently, this autoimmune limbic encephalitis has been noticed in many psychiatrists. We have experienced several cases with malignant catatonia having anti-NMDAR antibody without clinical signs of encephalitis. Thereafter, we have also found anti-NMDAR antibody positive patients of young females with acute florid psychiatric symptoms without clinical signs of encephalitis. The features of these patients mirror-those of "Atypical psychosis" proposed by Mitsuda in Japan, a notion derived from "Cycloid psychosis" conceptualized by German psychiatrist, Leonhard. Both cycloid and atypical psychosis have coinciding features of acute onset, emotional disturbances, psychomotor disturbances, alternations of consciousness, high prevalence in women and oriented premorbid personality. Both malignant catatonia and atypical psychosis have been known to be effectively treated with modified electro convulsion therapy (m-ECT). Our 5 cases with anti-NMDAR antibody, m-ECT treatments were effective. Infectious encephalitis is contra indication of m-ECT, but this autoimmune encephalitis would be careful indication. Schizophrenia is a common, heterogeneous, and complex disorder with unknown etiology. There is established evidence of NMDAR hypofunction as a central component of the functional disconnectivity; this is one of the most accepted models for schizophrenia. Moreover, autoimmune mechanisms have been proposed to be involved, at least in subgroups of schizophrenia patients. Further research of anti-NMDAR antibody and encephalitis would be important clues for the investigation of schizophrenia, catatonia and atypical psychosis.
View details for DOI 10.5692/clinicalneurol.54.1103
View details for PubMedID 25672720
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Greatly Increased Numbers of Histamine Cells in Human Narcolepsy with Cataplexy
ANNALS OF NEUROLOGY
2013; 74 (6): 786-793
Abstract
To determine whether histamine cells are altered in human narcolepsy with cataplexy and in animal models of this disease.Immunohistochemistry for histidine decarboxylase (HDC) and quantitative microscopy were used to detect histamine cells in human narcoleptics, hypocretin (Hcrt) receptor-2 mutant dogs, and 3 mouse narcolepsy models: Hcrt (orexin) knockouts, ataxin-3-orexin, and doxycycline-controlled-diphtheria-toxin-A-orexin.We found an average 64% increase in the number of histamine neurons in human narcolepsy with cataplexy, with no overlap between narcoleptics and controls. However, we did not see altered numbers of HDC cells in any of the animal models of narcolepsy.Changes in histamine cell numbers are not required for the major symptoms of narcolepsy, because all animal models have these symptoms. The histamine cell changes we saw in humans did not occur in the 4 animal models of Hcrt dysfunction we examined. Therefore, the loss of Hcrt receptor-2, of the Hcrt peptide, or of Hcrt cells is not sufficient to produce these changes. We speculate that the increased histamine cell numbers we see in human narcolepsy may instead be related to the process causing the human disorder. Although research has focused on possible antigens within the Hcrt cells that might trigger their autoimmune destruction, the present findings suggest that the triggering events of human narcolepsy may involve a proliferation of histamine-containing cells. We discuss this and other explanations of the difference between human narcoleptics and animal models of narcolepsy, including therapeutic drug use and species differences. Ann Neurol 2013;74:786-793.
View details for DOI 10.1002/ana.23968
View details for Web of Science ID 000329891100009
View details for PubMedID 23821583
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Histamine from Brain Resident MAST Cells Promotes Wakefulness and Modulates Behavioral States
PLOS ONE
2013; 8 (10)
Abstract
Mast cell activation and degranulation can result in the release of various chemical mediators, such as histamine and cytokines, which significantly affect sleep. Mast cells also exist in the central nervous system (CNS). Since up to 50% of histamine contents in the brain are from brain mast cells, mediators from brain mast cells may significantly influence sleep and other behaviors. In this study, we examined potential involvement of brain mast cells in sleep/wake regulations, focusing especially on the histaminergic system, using mast cell deficient (W/W(v)) mice. No significant difference was found in the basal amount of sleep/wake between W/W(v) mice and their wild-type littermates (WT), although W/W(v) mice showed increased EEG delta power and attenuated rebound response after sleep deprivation. Intracerebroventricular injection of compound 48/80, a histamine releaser from mast cells, significantly increased histamine levels in the ventricular region and enhanced wakefulness in WT mice, while it had no effect in W/W(v) mice. Injection of H1 antagonists (triprolidine and mepyramine) significantly increased the amounts of slow-wave sleep in WT mice, but not in W/W(v) mice. Most strikingly, the food-seeking behavior observed in WT mice during food deprivation was completely abolished in W/W(v) mice. W/W(v) mice also exhibited higher anxiety and depression levels compared to WT mice. Our findings suggest that histamine released from brain mast cells is wake-promoting, and emphasizes the physiological and pharmacological importance of brain mast cells in the regulation of sleep and fundamental neurobehavior.
View details for DOI 10.1371/journal.pone.0078434
View details for Web of Science ID 000326029300155
View details for PubMedID 24205232
View details for PubMedCentralID PMC3800008
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Wake-promoting effects of ONO-4127, a prostaglandin DP1 receptor antagonist, in hypocretin deficient narcoleptic mice
21st Congress of the European-Sleep-Research-Society
WILEY-BLACKWELL. 2012: 266–266
View details for Web of Science ID 000307963201192
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Predictors of Hypocretin (Orexin) Deficiency in Narcolepsy Without Cataplexy
SLEEP
2012; 35 (9): 1247-1255
Abstract
To compare clinical, electrophysiologic, and biologic data in narcolepsy without cataplexy with low (≤ 110 pg/ml), intermediate (110-200 pg/ml), and normal (> 200 pg/ml) concentrations of cerebrospinal fluid (CSF) hypocretin-1.University-based sleep clinics and laboratories.Narcolepsy without cataplexy (n = 171) and control patients (n = 170), all with available CSF hypocretin-1.Retrospective comparison and receiver operating characteristics curve analysis. Patients were also recontacted to evaluate if they developed cataplexy by survival curve analysis.The optimal cutoff of CSF hypocretin-1 for narcolepsy without cataplexy diagnosis was 200 pg/ml rather than 110 pg/ml (sensitivity 33%, specificity 99%). Forty-one patients (24%), all HLA DQB1*06:02 positive, had low concentrations (≤ 110 pg/ml) of CSF hypocretin-1. Patients with low concentrations of hypocretin-1 only differed subjectively from other groups by a higher Epworth Sleepiness Scale score and more frequent sleep paralysis. Compared with patients with normal hypocretin-1 concentration (n = 117, 68%), those with low hypocretin-1 concentration had higher HLA DQB1*06:02 frequencies, were more frequently non-Caucasians (notably African Americans), with lower age of onset, and longer duration of illness. They also had more frequently short rapid-eye movement (REM) sleep latency (≤ 15 min) during polysomnography (64% versus 23%), and shorter sleep latencies (2.7 ± 0.3 versus 4.4 ± 0.2 min) and more sleep-onset REM periods (3.6 ± 0.1 versus 2.9 ± 0.1 min) during the Multiple Sleep Latency Test (MSLT). Patients with intermediate concentrations of CSF hypocretin-1 (n = 13, 8%) had intermediate HLA DQB1*06:02 and polysomnography results, suggesting heterogeneity. Of the 127 patients we were able to recontact, survival analysis showed that almost half (48%) with low concentration of CSF hypocretin-1 had developed typical cataplexy at 26 yr after onset, whereas only 2% had done so when CSF hypocretin-1 concentration was normal. Almost all patients (87%) still complained of daytime sleepiness independent of hypocretin status.Objective (HLA typing, MSLT, and sleep studies) more than subjective (sleepiness and sleep paralysis) features predicted low concentration of CSF hypocretin-1 in patients with narcolepsy without cataplexy.
View details for DOI 10.5665/sleep.2080
View details for Web of Science ID 000308360100012
View details for PubMedID 22942503
View details for PubMedCentralID PMC3413802
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Muscleblind-like 2-Mediated Alternative Splicing in the Developing Brain and Dysregulation in Myotonic Dystrophy
NEURON
2012; 75 (3): 437-450
Abstract
The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDA receptor (NMDAR) synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, misregulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq, and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly misregulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program.
View details for DOI 10.1016/j.neuron.2012.05.029
View details for Web of Science ID 000307417700012
View details for PubMedID 22884328
View details for PubMedCentralID PMC3418517
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Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features
BMC PSYCHIATRY
2012; 12
Abstract
Causative role of encephalitis in major psychotic features, dyskinesias (particularly orofacial), seizures, and autonomic and respiratory changes has been recently emphasized. These symptoms often occur in young females with ovarian teratomas and are frequently associated with serum and CSF autoantibodies to the NMDA receptor (NMDAR).The study included a total of 61 patients from age 15 to 61 and was carried out between January 1, 2005, and Dec 31, 2010. The patients were divided into the following three clinical groups for comparison. Group A; Patients with typical clinical characteristics of anti-NMDAR encephalitis. Group B; Patients with narcolepsy with severe psychosis. Group C; Patients with schizophrenia or schizo-affective disorders.Ten out of 61 cases were anti-NMDAR antibody positive in typical encephalitis cases (group A: 3 of 5 cases) and cases in a broader range of psychiatric disorders including narcolepsy (group B: 3 of 5 cases) and schizophrenia (group C: 4 of 51 cases).In addition to 3 typical cases, we found 7 cases with anti-NMDAR antibody associated with various psychotic and sleep symptoms, which lack any noticeable clinical signs of encephalitis (seizures and autonomic symptoms) throughout the course of the disease episodes; this result suggest that further discussion on the nosology and pathophysiology of autoimmune-mediated atypical psychosis and sleep disorders is required.
View details for DOI 10.1186/1471-244X-12-37
View details for Web of Science ID 000308532100001
View details for PubMedID 22569157
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Time-course of cerebrospinal fluid histamine in the wake-consolidated squirrel monkey
JOURNAL OF SLEEP RESEARCH
2012; 21 (2): 189-194
Abstract
Central nervous system (CNS) histamine is low in individuals with narcolepsy, a disease characterized by severe fragmentation of both sleep and wake. We have developed a primate model, the squirrel monkey, with which we can examine the role of the CNS in the wake-consolidation process, as these primates are day-active, have consolidated wake and sleep and have cerebrospinal fluid (CSF) that is readily accessible. Using this model and three distinct protocols, we report herein on the role of CNS histamine in the wake consolidation process. CSF histamine has a robust daily rhythm, with a mean of 24.9 ± 3.29 pg mL(-1) , amplitude of 31.7 ± 6.46 pg mL(-1) and a peak at 17:49 ± 70.3 min (lights on 07:00-19:00 hours). These levels are not significantly affected by increases (up to 161 ± 40.4% of baseline) or decreases (up to 17.2 ± 2.50% of baseline) in locomotion. In direct contrast to the effects of sleep deprivation in non-wake-consolidating mammals, in whom CSF histamine increases, pharmacologically induced sleep (γ-hydroxybutyrate) and wake (modafinil) have no direct effects on CSF histamine concentrations. These data indicate that the time-course of histamine in CSF in the wake-consolidated squirrel monkey is robust against variation in activity and sleep and wake-promoting pharmacological compounds, and may indicate that histamine physiology plays a role in wake-consolidation such as is present in the squirrel monkey and humans.
View details for DOI 10.1111/j.1365-2869.2011.00957.x
View details for Web of Science ID 000301931500010
View details for PubMedID 21910776
View details for PubMedCentralID PMC3237761
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Familial narcolepsy in the Lipizzaner horse: a report of three fillies born to the same sire
VETERINARY QUARTERLY
2012; 32 (2): 99-102
Abstract
The occurrence of sleep disorder in three half sibling Lipizzaner is described. Sleepiness, swaying, stumbling, carpal joints buckling and falling down onto the carpal joints had been present since early foal age in all of them. Clinical signs had gradually reduced since the age of 2 years in cases 1 and 3. Sleepiness was induced by going out from the stable in adulthood. A physostigmine test was performed in all three affected horses and produced positive results in cases 1 and 3. The result of the test in case 2 was unclear due to the almost continuous sleepiness of the foal. Hypocretin-1 concentration in the cerebrospinal fluid was established using a standardised radioimmunoassay in case 1 (317.85 pg/mL), case 2 (303.43 pg/mL) and five adult control horses (275.2 ± 47.9 [SD] pg/mL) and was considered as normal in all horses. The sire of the affected horses has had 19 other registered offspring who did not show clinical signs of sleep disorder and also dams of all three cases produced healthy foals. Based on the demographic and clinical data together with the responses to the physostigmine challenges, the diagnosis of familial equine narcolepsy was made.
View details for DOI 10.1080/01652176.2012.714089
View details for Web of Science ID 000308251400005
View details for PubMedID 22889297
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SUPRACHIASMATIC NUCLEUS IS ESSENTIAL FOR SLEEP-IMPROVING EFFECTS OF GLYCINE
26th Annual Meeting of the Association-of-Professional-Sleep-Societies (APSS)
AMER ACAD SLEEP MEDICINE. 2012: A7–A7
View details for Web of Science ID 000312996500013
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Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome
NATURE MEDICINE
2011; 17 (12): 1657-U176
Abstract
Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Ca(v)1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca(2+)) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons. In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker. These findings provide strong evidence that Ca(v)1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome.
View details for DOI 10.1038/nm.2576
View details for PubMedID 22120178
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Recent Advances in the Treatment of Narcolepsy
CURRENT TREATMENT OPTIONS IN NEUROLOGY
2011; 13 (5): 437-457
Abstract
OPINION STATEMENT: A diagnosis of narcolepsy requires pharmacologic treatment in more than 90% of patients. Wake-promoting compounds are used to treat excessive daytime sleepiness (EDS), and anticataplectics are used for cataplexy. The treatment of EDS includes the use of amphetamine-like CNS stimulants (such as dextroamphetamine and methylphenidate), modafinil, and its R-enantiomer, armodafinil. Because of its high safety and low side-effect profiles, modafinil has become the first-line treatment of choice for EDS associated with narcolepsy. However, wake-promoting compounds do not improve cataplexy and dissociated manifestation of REM sleep, and so antidepressants (monoamine uptake inhibitors) are additionally used for the treatment of cataplexy and REM sleep abnormalities. Tricyclic antidepressants potently reduce REM sleep and thus have been used for the treatment of cataplexy and REM sleep abnormalities, but these have recently been replaced by more selective serotonin and/or noradrenaline uptake inhibitors with better side-effect profiles. As sodium oxybate (the approved formula of γ-hydroxybutyrate in the United States), given at night, improves both EDS and cataplexy, the number of US patients treated with sodium oxybate is increasing, while much progress has been made in understanding the modes of action of amphetamine-like CNS stimulants.
View details for DOI 10.1007/s11940-011-0137-6
View details for Web of Science ID 000294470600001
View details for PubMedID 21748548
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Refeeding after a 24-hour fasting deepens NREM sleep in a time-dependent manner
PHYSIOLOGY & BEHAVIOR
2011; 104 (3): 480-487
Abstract
Sleep/wake cycle is regulated by a variety of neuropeptides in the hypothalamus, a brain region that also regulates energy homeostasis and feeding behavior. Since circadian rhythms are affected by energy metabolism and feeding condition, we investigated whether changes in feeding regimen would influence sleep/wake parameters and body temperature. We monitored sleep and body temperature across three days of baseline (day 1), fasting (day 2), and refeeding (day 3) conditions under ordinary ambient temperature and employed different refeeding schedules. Refeeding at ZT1 following the 24-h fasting enhanced EEG delta power in NREM sleep. However, when the time of refeeding was set at either ZT7 or ZT12, the enhancement of EEG delta power was attenuated. The amount of NREM sleep was not largely affected by a 24-h fasting started at ZT1, although fasting that started at ZT12 changed the temporal distribution of NREM sleep. Hypothalamic nNOS mRNA level was increased both before and after refeeding at ZT1 compared with control condition, while there was no significant change in mice refed at ZT7. Level of NPY mRNA in the arcuate nucleus was increased before the refeeding only at ZT1. These results suggest that refeeding after a 24-h fasting makes NREM sleep deeper in a time-dependent manner.
View details for DOI 10.1016/j.physbeh.2011.05.011
View details for Web of Science ID 000293323700017
View details for PubMedID 21605579
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The Pathophysiologic Basis of Secondary Narcolepsy and Hypersomnia
CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS
2011; 11 (2): 235-241
Abstract
The symptoms of narcolepsy can occur during the course of other neurologic conditions (ie, symptomatic narcolepsy). Inherited disorders, tumors, and head trauma were the three most frequent causes for symptomatic narcolepsy. Other causes include multiple sclerosis (MS), vascular disorders, and encephalitis. Cerebrospinal fluid hypocretin-1 measures were carried out in some recent cases with symptomatic narcolepsy, and moderate decreases in hypocretin levels were seen in a large majority of these cases. Excessive daytime sleepiness (EDS) in these symptomatic cases was sometimes reversible with an improvement of the causative neurologic disorder and with an improvement of the hypocretin (orexin) status. Recently, we found that several symptomatic narcoleptic cases with MS show unique bilateral symmetric hypothalamic lesions associated with significant hypocretin ligand deficiency. In addition, these patients often share the clinical characteristics of neuromyelitis optica (NMO) and the detection of NMO-IgG (or anti-aquaporin-4 [AQP4] antibodies), suggesting a new clinical entity. Further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiologic mechanisms for occurrence of EDS and cataplexy.
View details for DOI 10.1007/s11910-011-0178-y
View details for Web of Science ID 000287926100017
View details for PubMedID 21298561
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Narcolepsy and cataplexy.
Handbook of clinical neurology
2011; 99: 783-814
View details for DOI 10.1016/B978-0-444-52007-4.00007-2
View details for PubMedID 21056228
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CHANGES IN BLOOD AMINO ACID LEVEL ASSOCIATED WITH SLEEP DEPRIVATION IN RATS
25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS)
AMER ACAD SLEEP MEDICINE. 2011: A107–A107
View details for Web of Science ID 000299834400307
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BRAIN RESIDENT MAST CELLS AFFECT SLEEP/WAKE PHYSIOLOGY AND PHARMACOLOGY
25th Anniversary Meeting of the Associated-Professional-Sleep-Societies (APSS)
AMER ACAD SLEEP MEDICINE. 2011: A45–A45
View details for Web of Science ID 000299834400122
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Hypothalamus, hypocretins/orexin, and vigilance control.
Handbook of clinical neurology
2011; 99: 765-782
Abstract
The hypothalamus has re-emerged as a key regulator of sleep and wakefulness, shifting the focus away from the brainstem and thalamocortical systems (ascending reticular activating systems). Several new sleep control systems in the hypothalamus and their interaction with the circadian pacemaker in the suprachiasmatic nucleus have been identified recently. More recently, deficiency of the hypothalamic peptide, hypocretin/orexin, has been found to be the major pathophysiological factor in human narcolepsy-cataplexy, the sleep disorder characterized by excessive daytime sleepiness and rapid eye movement sleep abnormalities. The results from a series of experiments suggest that the hypocretin system is involved in the maintenance of wakefulness and stabilizes the vigilance states. The hypocretin system also plays a role in the link between sleep and other fundamental hypothalamic functions, such as the regulation of food intake, metabolism, hormone release, and temperature. Sleep deprivation is known to alter hormone release, increase body temperature, stimulate appetite, and activate the sympathetic nervous system. Sleep control systems within the hypothalamus may therefore be closely integrated with homeostatic systems needed for survival. In this chapter, the role of the hypothalamus in vigilance control is discussed, with a particular emphasis on the hypocretins/orexin system.
View details for DOI 10.1016/B978-0-444-52007-4.00006-0
View details for PubMedID 21056227
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Tuning arousal with optogenetic modulation of locus coeruleus neurons
NATURE NEUROSCIENCE
2010; 13 (12): 1526-U117
Abstract
Neural activity in the noradrenergic locus coeruleus correlates with periods of wakefulness and arousal. However, it is unclear whether tonic or phasic activity in these neurons is necessary or sufficient to induce transitions between behavioral states and to promote long-term arousal. Using optogenetic tools in mice, we found that there is a frequency-dependent, causal relationship among locus coeruleus firing, cortical activity, sleep-to-wake transitions and general locomotor arousal. We also found that sustained, high-frequency stimulation of the locus coeruleus at frequencies of 5 Hz and above caused reversible behavioral arrests. These results suggest that the locus coeruleus is finely tuned to regulate organismal arousal and that bursts of noradrenergic overexcitation cause behavioral attacks that resemble those seen in people with neuropsychiatric disorders.
View details for DOI 10.1038/nn.2682
View details for Web of Science ID 000284525800018
View details for PubMedID 21037585
View details for PubMedCentralID PMC3174240
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Clinical and Therapeutic Aspects of Childhood Narcolepsy-Cataplexy: A Retrospective Study of 51 Children
SLEEP
2010; 33 (11): 1457-1464
Abstract
to report on symptoms and therapies used in childhood narcolepsy-cataplexy.retrospective series of 51 children who completed the Stanford Sleep Inventory. HLA-DQB1*0602 typing (all tested, and 100% positive), polysomnography or Multiple Sleep Latency Test (76%), and cerebrospinal fluid hypocretin-1 measurements (26%, all with low levels) were also conducted. Prospective data on medication response was collected in 78% using a specially designed questionnaire.patients were separated into children with onset of narcolepsy prior to (53%), around (29%), and after (18%) puberty. None of the children had secondary narcolepsy. Clinical features were similar across puberty groups, except for sleep paralysis, which increased in frequency with age. Common features included excessive weight gain (84% ≥ 4 kg within 6 months of onset of narcolepsy) and earlier puberty (when compared with family members), notably in subjects who gained the most weight. Streptococcus-positive throat infections were reported in 20% of cases within 6 months of onset of narcolepsy. Polysomnographic features were similar across groups, but 3 prepubertal children did not meet Multiple Sleep Latency Test diagnostic criteria. Regarding treatment, the most used and continued medications were modafinil (84% continued), sodium oxybate (79%), and venlafaxine (68%). Drugs such as methylphenidate, tricyclic antidepressants, or selective serotonin reuptake inhibitors were often tried but rarely continued. Modafinil was reported to be effective for treating sleepiness, venlafaxine for cataplexy, and sodium oxybate for all symptoms, across all puberty groups. At the conclusion of the study, half of children with prepubertal onset of narcolepsy were treated "off label" with sodium oxybate alone or with the addition of one other compound. In older children, however, most patients needed more than 2 drugs.this study reports on the clinical features of childhood narcolepsy and documents the safe use of treatments commonly used in adults in young children.
View details for Web of Science ID 000285212600009
View details for PubMedID 21102987
View details for PubMedCentralID PMC2954695
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Effects of sleep on the cardiovascular and thermoregulatory systems: a possible role for hypocretins
JOURNAL OF APPLIED PHYSIOLOGY
2010; 109 (4): 1053-1063
Abstract
Sleep influences the cardiovascular, endocrine, and thermoregulatory systems. Each of these systems may be affected by the activity of hypocretin (orexin)-producing neurons, which are involved in the etiology of narcolepsy. We examined sleep in male rats, either hypocretin neuron-ablated orexin/ataxin-3 transgenic (narcoleptic) rats or their wild-type littermates. We simultaneously monitored electroencephalographic and electromyographic activity, core body temperature, tail temperature, blood pressure, electrocardiographic activity, and locomotion. We analyzed the daily patterns of these variables, parsing sleep and circadian components and changes between states of sleep. We also analyzed the baroreceptor reflex. Our results show that while core temperature and heart rate are affected by both sleep and time of day, blood pressure is mostly affected by sleep. As expected, we found that both blood pressure and heart rate were acutely affected by sleep state transitions in both genotypes. Interestingly, hypocretin neuron-ablated rats have significantly lower systolic and diastolic blood pressure during all sleep stages (non-rapid eye movement, rapid eye movement) and while awake (quiet, active). Thus, while hypocretins are critical for the normal temporal structure of sleep and wakefulness, they also appear to be important in regulating baseline blood pressure and possibly in modulating the effects of sleep on blood pressure.
View details for DOI 10.1152/japplphysiol.00516.2010
View details for Web of Science ID 000285344900016
View details for PubMedID 20705949
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Effects of Paraxanthine and Caffeine on Sleep, Locomotor Activity, and Body Temperature in Orexin/Ataxin-3 Transgenic Narcoleptic Mice
SLEEP
2010; 33 (7): 930-942
Abstract
Caffeine, an adenosine A1 and A2a receptor antagonist, is a widely consumed stimulant and also used for the treatment of hypersomnia; however, the wake-promoting potency of caffeine is often not strong enough, and high doses may induce side effects. Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine.We evaluated the wake-promoting efficacy of paraxanthine, caffeine, and a reference wake-promoting compound, modafinil, in a mice model of narcolepsy, a prototypical disease model of hypersomnia. Orexin/ataxin-3 transgenic (TG) and wild-type (WT) mice were subjected to oral administration (at ZT 2 and ZT14) of 3 doses of paraxanthine, caffeine, modafinil, or vehicle.Paraxanthine, caffeine, and modafinil significantly promoted wakefulness in both WT and narcoleptic TG mice and proportionally reduced NREM and REM sleep in both genotypes. The wake-promoting potency of 100 mg/kg p.o. of paraxanthine during the light period administration roughly corresponds to that of 200 mg/kg p.o. of modafinil. The wake-promoting potency of paraxanthine is greater and longer lasting than that of the equimolar concentration of caffeine, when the drugs were administered during the light period. The wake-promotion by paraxanthine, caffeine, and modafinil are associated with an increase in locomotor activity and body temperature. However, the higher doses of caffeine and modafinil, but not paraxanthine, induced hypothermia and reduced locomotor activity, thereby confirming the lower toxicity of paraxanthine. Behavioral evaluations of anxiety levels in WT mice revealed that paraxanthine induced less anxiety than caffeine did.Because it is also reported to provide neuroprotection, paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases.
View details for Web of Science ID 000279365600013
View details for PubMedID 20614853
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Loss of polyubiquitin gene Ubb leads to metabolic and sleep abnormalities in mice
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
2010; 36 (4): 285-299
Abstract
Ubiquitin performs essential roles in a myriad of signalling pathways required for cellular function and survival. Recently, we reported that disruption of the stress-inducible ubiquitin-encoding gene Ubb reduces ubiquitin content in the hypothalamus and leads to adult-onset obesity coupled with a loss of arcuate nucleus neurones and disrupted energy homeostasis in mice. Neuropeptides expressed in the hypothalamus control both metabolic and sleep behaviours. In order to demonstrate that the loss of Ubb results in broad hypothalamic abnormalities, we attempted to determine whether metabolic and sleep behaviours were altered in Ubb knockout mice.Metabolic rate and energy expenditure were measured in a metabolic chamber, and sleep stage was monitored via electroencephalographic/electromyographic recording. The presence of neurodegeneration and increased reactive gliosis in the hypothalamus were also evaluated.We found that Ubb disruption leads to early-onset reduced activity and metabolic rate. Additionally, we have demonstrated that sleep behaviour is altered and sleep homeostasis is disrupted in Ubb knockout mice. These early metabolic and sleep abnormalities are accompanied by persistent reactive gliosis and the loss of arcuate nucleus neurones, but are independent of neurodegeneration in the lateral hypothalamus.Ubb knockout mice exhibit phenotypes consistent with hypothalamic dysfunction. Our data also indicate that Ubb is essential for the maintenance of the ubiquitin levels required for proper regulation of metabolic and sleep behaviours in mice.
View details for DOI 10.1111/j.1365-2990.2009.01057.x
View details for Web of Science ID 000277712100003
View details for PubMedID 20002312
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Hypocretin Ligand Deficiency in Narcolepsy: Recent Basic and Clinical Insights
CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS
2010; 10 (3): 180-189
Abstract
Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. Both sporadic and familial forms exist in humans. Recently, the major pathophysiology of human narcolepsy was indicated, based on discovery, through animal study, of narcolepsy genes involved in the pathology of hypocretin/orexin ligand and its receptor. Hypocretin ligand deficiency is found in most patients with narcolepsy with cataplexy. This deficiency likely is the result of postnatal cell death of hypocretin neurons, and involvement of autoimmune mechanisms is suggested. Hypocretin deficiency also is found in symptomatic narcolepsy and excessive daytime sleepiness with neurologic conditions, including immune-mediated neurologic disorders. These findings have significant clinical relevance and promote understanding of hypocretin cell death mechanisms. Already, discoveries in humans have led to a new diagnostic test for narcolepsy. Currently, hypocretin replacement therapy has emerged as a promising therapeutic option, and experiments using gene therapy and cell transplantation are in progress.
View details for DOI 10.1007/s11910-010-0100-z
View details for Web of Science ID 000278111700004
View details for PubMedID 20425033
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Emerging treatments for narcolepsy and its related disorders
EXPERT OPINION ON EMERGING DRUGS
2010; 15 (1): 139-158
Abstract
Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and nocturnal sleep disruption. Non-pharmacological treatments (i.e., behavioral modification) are often helpful for the clinical management of narcoleptic patients. As these symptoms are often disabling, most patients need life-long treatments. Over 90% of diagnosed narcoleptic patients are currently prescribed medications to control their symptoms; however, available treatments are merely symptomatic.This review presents a description of the clinical symptoms of narcolepsy, followed by a discussion of the state-of-the-art knowledge regarding the disorder and related emerging treatments. In preparing this review, an extensive literature search was conducted using Pubmed. Only selected references from 1970 to 2008 are cited.This review focuses on emerging treatments for human narcolepsy, and the reader will gain significant knowledge of current and future treatment for this and related disorders. Traditionally, amphetamine-like stimulants (i.e., dopaminergic release enhancers) have been used for clinical management to improve EDS, and tricyclic antidepressants have been used as anticataplectics. However, treatments have recently evolved which utilize better tolerated compounds, such as modafinil (for EDS) and adrenergic/serotonergic selective reuptake inhibitors (as anticataplectics). In addition, night time administration of a short-acting sedative, gamma-hydroxybutyrate, has been used for the treatment for EDS and cataplexy. As a large majority of human narcolepsy is hypocretin peptide deficient, hypocretin replacement therapy may also be a new therapeutic option; yet, this option is still unavailable. In addition to the hypocretin-based therapy, a series of new treatments are currently being tested in animal and/or humans models. These potential options include novel stimulant and anticataplectic drugs as well as immunotherapy, based on current knowledge of the pathophysiology of narcolepsy with cataplexy.We expect that more pathophysiology-based treatments, capable of curing and/or preventing narcolepsy and related diseases, will be available in near future. As cases of EDS, associated with other neurological conditions (i.e., symptomatic narcolepsy or narcolepsy due to medical conditions), are often linked with hypocretin deficiency, these novel therapeutic options may also be applied to treatment of these disabling conditions.
View details for DOI 10.1517/14728210903559852
View details for Web of Science ID 000276031100010
View details for PubMedID 20166851
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Hypocretin/orexin and narcolepsy: new basic and clinical insights
ACTA PHYSIOLOGICA
2010; 198 (3): 209-222
Abstract
Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, sleep paralysis and hypnagogic hallucinations. Both sporadic (95%) and familial (5%) forms of narcolepsy exist in humans. The major pathophysiology of human narcolepsy has been recently discovered based on the discovery of narcolepsy genes in animals; the genes involved in the pathology of the hypocretin/orexin ligand and its receptor. Mutations in hypocretin-related genes are rare in humans, but hypocretin ligand deficiency is found in a large majority of narcolepsy with cataplexy. Hypocretin ligand deficiency in human narcolepsy is probably due to the post-natal cell death of hypocretin neurones. Although a close association between human leucocyte antigen (HLA) and human narcolepsy with cataplexy suggests an involvement of autoimmune mechanisms, this has not yet been proved. Hypocretin deficiency is also found in symptomatic cases of narcolepsy and EDS with various neurological conditions, including immune-mediated neurological disorders, such as Guillain-Barre syndrome, MA2-positive paraneoplastic syndrome and neuromyelitis optica (NMO)-related disorder. The findings in symptomatic narcoleptic cases may have significant clinical relevance to the understanding of the mechanisms of hypocretin cell death and choice of treatment option. The discoveries in human cases lead to the establishment of the new diagnostic test of narcolepsy (i.e. low cerebrospinal fluid hypocretin-1 levels for 'narcolepsy with cataplexy' and 'narcolepsy due to medical condition'). As a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress.
View details for DOI 10.1111/j.1748-1716.2009.02012.x
View details for Web of Science ID 000274147900004
View details for PubMedID 19555382
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THE NEUROCHEMISTRY OF AWAKENING: FINDINGS FROM SLEEP DISORDER NARCOLEPSY
SCIENCE OF AWAKENING
2010; 93: 229-255
Abstract
Recent progress in our understanding of the pathophysiology of excessive sleepiness (EDS) is particularly indebted to the 1999 discovery of narcolepsy genes (i.e., hypocretin receptor and peptide genes) in animals and the subsequent discovery of hypocretin ligand deficiency in idiopathic cases of human narcolepsy-cataplexy. Hypocretin deficiency is also involved in many cases of symptomatic narcolepsy and EDS. Changes in other neurotransmitter systems (such as monoamines and acetylcholine) previously reported in these conditions are likely to be secondary to the impaired hypocretin neurotransmission; however, these may also mediate the sleep abnormalities seen in hypocretin deficient narcolepsy. The pathophysiology of hypocretin non-deficient narcolepsy is debated. Similarly, the pathophysiology of idiopathic hypersomnia, another defined primary hypersomnia, is largely unknown. This chapter discusses our current understanding of the neurochemistry of EDS, a disease of awakening.
View details for DOI 10.1016/S0074-7742(10)93010-9
View details for Web of Science ID 000284504400010
View details for PubMedID 20970008
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WAKE PROMOTING EFFECTS OF SELECTIVE ADENOSINE RECEPTOR ANTAGONISTS IN OREXIN/ATAXIN-3 NARCOLEPTIC MICE
AMER ACAD SLEEP MEDICINE. 2010: A54–A54
View details for Web of Science ID 000208208000155
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Symptomatic Narcolepsy in Patients With Neuromyelitis Optica and Multiple Sclerosis New Neurochemical and Immunological Implications
ARCHIVES OF NEUROLOGY
2009; 66 (12): 1563-1566
Abstract
To characterize factors that contribute to symptomatic narcolepsy and excessive daytime sleepiness in neuromyelitis optica and multiple sclerosis.Japanese university hospitals.Case study.Seven Japanese patients whose initial diagnoses were multiple sclerosis and who were exhibiting excessive daytime sleepiness.Lesions on magnetic resonance imaging, cerebrospinal fluid hypocretin-1 levels, and serum anti-aquaporin 4 (AQP4) antibody titer.Bilateral and symmetrical hypothalamic lesions associated with marked or moderate hypocretin deficiency were found in all 7 cases. Four of these patients met the International Classification of Sleep Disorders 2 narcolepsy criteria. Three patients, including 2 patients with narcolepsy, were seropositive for anti-AQP4 antibody and diagnosed as having neuromyelitis optica-related disorder.Since AQP4 is highly expressed in the hypothalamic periventricular regions, an immune attack on AQP4 may be partially responsible for the bilateral and hypothalamic lesions and hypocretin deficiency in narcolepsy/excessive daytime sleepiness associated with autoimmune demyelinating diseases.
View details for Web of Science ID 000272554200020
View details for PubMedID 20008665
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Amyloid-beta Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle
SCIENCE
2009; 326 (5955): 1005-1007
Abstract
Amyloid-beta (Abeta) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. Abeta aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of Abeta. Using in vivo microdialysis in mice, we found that the amount of ISF Abeta correlated with wakefulness. The amount of ISF Abeta also significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, Abeta plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease.
View details for DOI 10.1126/science.1180962
View details for Web of Science ID 000271712300043
View details for PubMedID 19779148
View details for PubMedCentralID PMC2789838
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Rebound Hypersomnolence, Stimulant Abuse, and DAT-Mediated Dopamine Release
SLEEP
2009; 32 (11): 1407-1409
View details for Web of Science ID 000271693700001
View details for PubMedID 19928377
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Orexin Neurons Are Necessary for the Circadian Control of REM Sleep
SLEEP
2009; 32 (9): 1127-1134
Abstract
The orexin-producing neurons are hypothesized to be essential for the circadian control of sleep/wake behavior, but it remains unknown whether these rhythms are mediated by the orexin peptides or by other signaling molecules released by these neurons such as glutamate or dynorphin. To determine the roles of these neurotransmitters, we examined the circadian rhythms of sleep/wake behavior in mice lacking the orexin neurons (ataxin-3 [Atx] mice) and mice lacking just the orexin neuropeptides (orexin knockout [KO] mice).We instrumented mice for recordings of sleep-wake behavior, locomotor activity (LMA), and body temperature (Tb) and recorded behavior after 6 days in constant darkness.The amplitude of the rapid eye movement (REM) sleep rhythm was substantially reduced in Atx mice but preserved in orexin KO mice. This blunted rhythm in Atx mice was caused by an increase in the amount of REM sleep during the subjective night (active period) due to more transitions into REM sleep and longer REM sleep episodes. In contrast, the circadian variations of Tb, LMA, Wake, non-REM sleep, and cataplexy were normal, suggesting that the circadian timekeeping system and other output pathways are intact in both Atx and KO mice.These results indicate that the orexin neurons are necessary for the circadian suppression of REM sleep. Blunting of the REM sleep rhythm in Atx mice but not in orexin KO mice suggests that other signaling molecules such as dynorphin or glutamate may act in concert with orexins to suppress REM sleep during the active period.
View details for Web of Science ID 000269469700004
View details for PubMedID 19750917
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The Transcriptional Repressor DEC2 Regulates Sleep Length in Mammals
SCIENCE
2009; 325 (5942): 866-870
Abstract
Sleep deprivation can impair human health and performance. Habitual total sleep time and homeostatic sleep response to sleep deprivation are quantitative traits in humans. Genetic loci for these traits have been identified in model organisms, but none of these potential animal models have a corresponding human genotype and phenotype. We have identified a mutation in a transcriptional repressor (hDEC2-P385R) that is associated with a human short sleep phenotype. Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time- and sleep deprivation-dependent manner. These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.
View details for DOI 10.1126/science.1174443
View details for Web of Science ID 000269242400044
View details for PubMedID 19679812
View details for PubMedCentralID PMC2884988
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Specificity of direct transition from wake to REM sleep in orexin/ataxin-3 transgenic narcoleptic mice
EXPERIMENTAL NEUROLOGY
2009; 217 (1): 46-54
Abstract
To create operational criteria for polygraphic assessments of direct transitions from wake to REM sleep (DREM), as a murine analog of human cataplexy, we have analyzed DREM episodes in congenic lines of orexin/ataxin-3 transgenic [TG] mice and wild-type littermates. The sleep stage of each 10-second epoch was visually scored using our standard criteria. Specificity of DREM for narcoleptic TG mice and sensitivity to detect DREM was evaluated using different DREM criteria. We found that DREM transitions by 10-second epoch scoring are not specific for narcoleptic TG mice and also occur in WT mice during light period. These wake-to-REM transitions in WT mice (also seen in TG mice during light period) were characteristically different from DREM transitions in TG mice during dark period; they tended to occur as brief bouts of wakefulness interrupting extended episodes of REM sleep, suggesting that these transitions do not represent abnormal manifestations of REM sleep. We therefore defined the DREM transitions by requiring a minimum number of preceding wake epochs. Requiring no fewer than four consecutive epochs of wakefulness produced the best combination of specificity (95.9%) and sensitivity (66.0%). By definition, DREM in dark-period is 100% specific to narcolepsy and was 95.9% specific overall. In addition, we found that desipramine, a trycyclic anticataplectic, potently reduces DREM, while two wake-promoting compounds have moderate (D-amphetamine) and no (modafinil) effect on DREM; the effects mirror the anticataplectic effects of these compounds reported in canine and human narcolepsy. Our definition of DREM in murine narcolepsy may provide good electrophysiological measures for cataplexy-equivalent episodes.
View details for DOI 10.1016/j.expneurol.2009.01.015
View details for Web of Science ID 000265859000007
View details for PubMedID 19416673
View details for PubMedCentralID PMC2679850
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Decreased CSF Histamine in Narcolepsy With and Without Low CSF Hypocretin-1 in Comparison to Healthy Controls
SLEEP
2009; 32 (2): 175-180
Abstract
To examine whether cerebrospinal fluid (CSF) histamine contents are altered in human narcolepsy and whether these alterations are specific to hypocretin deficiency, as defined by low CSF hypocretin-1.Patients meeting the ICSD-2 criteria for narcolepsy with and without cataplexy and who had CSF hypocretin-1 results available were selected from the Stanford Narcolepsy Database on the basis of CSF availability and adequate age and sex matching across 3 groups: narcolepsy with low CSF hypocretin-1 (n=34, 100% with cataplexy), narcolepsy without low CSF hypocretin-1 (n=24, 75% with cataplexy), and normal controls (n=23). Low CSF hypocretin-1 was defined as CSF < or =110 pg/mL (1/3 of mean control values). Six of 34 patients with low CSF hypocretin-1, six of 24 subjects with normal CSF hypocretin-1, and all controls were unmedicated at the time of CSF collection. CSF histamine was measured in all samples using a fluorometric HPLC system.Mean CSF histamine levels were: 133.2 +/- 20.1 pg/mL in narcoleptic subjects with low CSF hypocretin-1, 233.3 +/- 46.5 pg/mL in patients with normal CSF hypocretin-1 (204.9 +/- 89.7 pg/mL if only patients without cataplexy are included), and 300.5 +/- 49.7 pg/mL in controls, reaching statistically significant differences between the 3 groups.CSF histamine levels are reduced in human narcolepsy. The reduction of CSF histamine levels was more evident in the cases with low CSF hypocretin-1, and levels were intermediate in other narcolepsy cases. As histamine is a wake-promoting amine known to decrease during sleep, decreased histamine could either passively reflect or partially mediate daytime sleepiness in these pathologies.
View details for Web of Science ID 000262890300008
View details for PubMedID 19238804
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CSF Histamine Contents in Narcolepsy, Idiopathic Hypersomnia and Obstructive Sleep Apnea Syndrome
SLEEP
2009; 32 (2): 181-187
Abstract
To (1) replicate our prior result of low cerebrospinal fluid (CSF) histamine levels in human narcolepsy in a different sample population and to (2) evaluate if histamine contents are altered in other types of hypersomnia with and without hypocretin deficiency.Cross sectional studies.Sixty-seven narcolepsy subjects, 26 idiopathic hypersomnia (IHS) subjects, 16 obstructive sleep apnea syndrome (OSAS) subjects, and 73 neurological controls were included. All patients were Japanese. Diagnoses were made according to ICSD-2.We found significant reductions in CSF histamine levels in hypocretin deficient narcolepsy with cataplexy (mean +/- SEM; 176.0 +/- 25.8 pg/mL), hypocretin non-deficient narcolepsy with cataplexy (97.8 +/- 38.4 pg/mL), hypocretin non-deficient narcolepsy without cataplexy (113.6 +/- 16.4 pg/mL), and idiopathic hypersomnia (161.0 +/- 29.3 pg/ mL); the levels in OSAS (259.3 +/- 46.6 pg/mL) did not statistically differ from those in the controls (333.8 +/- 22.0 pg/mL). Low CSF histamine levels were mostly observed in non-medicated patients; significant reductions in histamine levels were evident in non-medicated patients with hypocretin deficient narcolepsy with cataplexy (112.1 +/- 16.3 pg/ mL) and idiopathic hypersomnia (143.3 +/- 28.8 pg/mL), while the levels in the medicated patients were in the normal range.The study confirmed reduced CSF histamine levels in hypocretin-deficient narcolepsy with cataplexy. Similar degrees of reduction were also observed in hypocretin non-deficient narcolepsy and in idiopathic hypersomnia, while those in OSAS (non central nervous system hypersomnia) were not altered. The decrease in histamine in these subjects were more specifically observed in non-medicated subjects, suggesting CSF histamine is a biomarker reflecting the degree of hypersomnia of central origin.
View details for Web of Science ID 000262890300009
View details for PubMedID 19238805
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FUNCTIONAL ROLE OF BRAIN MAST CELL-DERIVED HISTAMINE OF MICE IN SLEEP-WAKE REGULATION
23rd Annual Meeting of the Associated-Professional-Sleep-Societies (APSS)
AMER ACAD SLEEP MEDICINE. 2009: A6–A7
View details for Web of Science ID 000265542000021
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[The US Government's effort in decreasing the cost of sleep-related problems and its outcome].
Journal of UOEH
2008; 30 (3): 329-352
Abstract
Sleepiness and inattention caused by sleep and circadian rhythm disorders or inadequate sleep habits adversely affect workers in many industries as well as the general public, and these disorders are likely to lead to public health and safety problems and adversely affect civilian life. Evidence is accumulating that these sleep related problems are contributing factors not only in many errors of judgement and accidents, but also related to some highly prevalent diseases, such as diabetes, obesity and hypertension. For each of these societal concerns, sleep science must be translated to the general public and to those in policy positions for improving public policy and public health awareness. In the United State, the National Commission for Sleep Disorders Research (established by the US Congress in 1998) completed a comprehensive report of its findings in 1993 to address these problems. The commission estimated that sleep disorders and sleepiness cost the United States $50 billion and called for permanent and concentrated efforts in expanding basic and clinical research on sleep disorders as well as in improving public awareness of the dangers of inadequate sleep hygiene. As a result of these efforts, the number of sleep centers has increased steadily and the total of the NIH (National Institutes of Health) funding for sleep research has also grown. In response to this progress in the US (together with appeals by Japanese Sleep Specialists), the Science Council of Japan published "The Recommendation of Creation of Sleep Science and Progression of Research" in 2002. In this article, we introduce and detail to the Japanese readers the US Government's efforts focusing on the report of the National Commission for Sleep Disorders Research, and we believe that the US Government's effort is a good example for the Japanese society to follow.
View details for PubMedID 18783014
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Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy
SLEEP
2008; 31 (8): 1119-1126
Abstract
To determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy.Animal and human study. We measured hcrtR1 and hcrtR2 expression in the frontal cortex and pons using the RT-PCR method in murine models (8-week-old and 27-week-old orexin/ataxin-3 transgenic (TG) hypocretin cell ablated mice and wild-type mice from the same litter, 10 mice for each group), in canine models (8 genetically narcoleptic Dobermans with null mutations in the hcrtR2, 9 control Dobermans, 3 sporadic ligand-deficient narcoleptics, and 4 small breed controls), and in humans (5 narcolepsy-cataplexy patients with hypocretin deficiency (average age 77.0 years) and 5 control subjects (72.6 years).27-week-old (but not 8-week-old) TG mice showed significant decreases in hcrtR1 expression, suggesting the influence of the long-term ligand loss on the receptor expression. Both sporadic narcoleptic dogs and human narcolepsy-cataplexy subjects showed a significant decrease in hcrtR1 expression, while declines in hcrtR2 expression were not significant in these cases. HcrtR2-mutated narcoleptic Dobermans (with normal ligand production) showed no alteration in hcrtR1 expression.Moderate declines in hcrtR expressions, possibly due to long-term postnatal loss of ligand production, were observed in hypocretin-ligand deficient narcoleptic subjects. These declines are not likely to be progressive and complete. The relative preservation of hcrtR2 expression also suggests that hypocretin based therapies are likely to be a viable therapeutic options in human narcolepsy-cataplexy.
View details for Web of Science ID 000258111000009
View details for PubMedID 18714784
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Armodafinil for excessive daytime sleepiness
DRUGS OF TODAY
2008; 44 (6): 395-414
Abstract
Armodafinil is the (R)-enantiomer of the wakepromoting compound modafinil (racemic), with a considerably longer half-life of 10-15 hours. Armodafinil (developed by Cephalon, Frazer, PA, USA) was approved in June 2007 for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea syndrome and shift work disorder, and the indications are the same as those for modafinil. Like modafinil, the mechanisms of action of armodafinil are not fully characterized and are under debate. Clinical trials in these sleep disorders demonstrated an enhanced efficacy for wake promotion (wake sustained for a longer time period using doses lower than those of modafinil). The safety profile is consistent with that of modafinil, and armodafinil is well tolerated by the patients. Like modafinil, armodafinil is classified as a non-narcotic Schedule IV compound. Many patients with excessive sleepiness may prefer the longer duration of effect and may have better compliance (with low doses) with armodafinil. The commercial challenge to armodafinil may come from generic modafinil, which may become available in 2012, as well as from classical amphetamine and amphetamine-like compounds (for the treatment of narcolepsy).
View details for DOI 10.1358/dot.2008.44.5.1195861
View details for Web of Science ID 000257604100001
View details for PubMedID 18596995
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Sleep and EEG features in genetic models of Down syndrome
NEUROBIOLOGY OF DISEASE
2008; 30 (1): 1-7
Abstract
Down syndrome is characterized by a host of behavioral abnormalities including sleep disturbances. Sleep and EEG was studied at the age of 3 months in two mouse models of the condition, Ts65Dn and Ts1Cje, carrying one extra copy of partially overlapping segments of the mmu chromosome 16 (equivalent to the human chromosome 21). We found that the Ts65Dn mice showed increased waking amounts at the expense of non-REM sleep, increased theta power during sleep and a delayed sleep rebound after sleep deprivation. In contrast, Ts1Cje had limited sleep and EEG abnormalities, showing only a delayed sleep rebound after sleep deprivation and no difference in theta power. We previously found that mice over-expressing the human APPwt transgene, a gene triplicated in Ts65Dn but not Ts1Cje, also show increased wake and theta power during sleep. These results demonstrate abnormalities in sleep and EEG in Ts65Dn mice and underscore a possible correlation between App overexpression and hippocampal theta oscillations.
View details for DOI 10.1016/j.nbd.2007.07.014
View details for Web of Science ID 000254665100001
View details for PubMedID 18282758
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CSF histamine levels in rats reflect the central histamine neurotransmission
NEUROSCIENCE LETTERS
2008; 430 (3): 224-229
Abstract
Reduced cerebrospinal fluid (CSF) histamine levels were found in human hypersomnia. To evaluate the functional significance of changes in CSF histamine levels, we measured the levels in rats across 24h, after the administration of wake-promoting compounds modafinil, amphetamine, and thioperamide, and after sleep deprivation and food deprivation. Thioperamide significantly increased CSF histamine levels with little effects on locomotor activation. Both modafinil and amphetamine markedly increased the locomotor activity, but had no effects on histamine. The levels are high during active period and are markedly elevated by sleep deprivation, but not by food deprivation. Our study suggests that CSF histamine levels in rats reflect the central histamine neurotransmission and vigilance state changes, providing deeper insight into the human data.
View details for DOI 10.1016/j.neulet.2007.11.002
View details for Web of Science ID 000253071800008
View details for PubMedID 18077091
View details for PubMedCentralID PMC2266592
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CSF orexin-A/hypocretin-1 concentrations in patients with intracerebral hemorrhage (ICH)
REGULATORY PEPTIDES
2008; 145 (1-3): 60-64
Abstract
Orexins/hypocretins are neuropeptides that have various physiological effects, including the regulation of both the feeding behavior neuroendocrine functions and sleep-wakefulness cycle. Recent studies have suggested that the orexin system may also be involved in neuronal damage in the clinical setting and animal experiments. The aim of this study was to examine the role of the hypothalamic orexin-A/hypocretin-1 system in patients with intracerebral hemorrhage (ICH). The CSF orexin-A/hypocretin-1 levels were measured in 11 ICH patients. CSF orexin-A/hypocretin-1 levels were low in ICH patients during the 13 days following the ICH event. The mean CSF orexin-A/hypocretin-1 levels were 61.1+/-22.3 (S.D.) pg/ml (range 27.5-106.9 pg/ml). The decreasing in the CSF orexin-A/hypocretin-1 levels was not related to the severity of ICH. The CSF orexin-A/hypocretin-1 levels were lower in the thalamic hemorrhage patients than those in other patients (48.5+/-23.3 pg/ml vs. 65.2+/-21.2 pg/ml; p=0.03.) These data indicate that orexin-A/hypocretin-1 may therefore play an important role in the various physiological responses including sleep, feeding, and the overall metabolism in ICH patients.
View details for DOI 10.1016/j.regpep.2007.08.005
View details for Web of Science ID 000252997800012
View details for PubMedID 17868933
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CSF histamine levels in narcolepsy, idiopathic hypersomnia and obstructive sleep APNEA syndrome
22nd Annual Meeting of the Associated-Professional-Sleep-Societies
AMER ACAD SLEEP MEDICINE. 2008: A215–A215
View details for Web of Science ID 000255419001085
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The hypocretin/orexin receptor: therapeutic prospective in sleep disorders
EXPERT OPINION ON INVESTIGATIONAL DRUGS
2007; 16 (11): 1785-1797
Abstract
The hypocretins (also known as orexins) and their receptors are the focus of many investigators as sites for therapeutic intervention in a number of endocrinologic, neurologic and sleep disorders. The interest for the hypocretin system is highlighted by a recent discovery that a human sleep disorder, narcolepsy, is tightly linked with the deficiency of hypocretin peptides. This finding suggests that hypocretin replacement is a promising new therapeutic intervention for human narcolepsy and related disorders, but this will only become possible when small-molecule (i.e., non-peptide) hypocretin receptor agonists become available. In contrast, high-throughput screening efforts in hypocretin receptor drug discovery programs by a number of pharmaceutical companies have already identified novel small-molecule hypocretin receptor antagonists and these antagonists may be used for the treatment of insomnia, especially for sleep-initiation problems. This is because hypocretin-deficient narcoleptic subjects show very short sleep latency and the blockade of the hypocretin receptor may induce a similar sleep symptom. At least two hypocretin receptor antagonists (ACT-078573 and GW-649868) are presently under development for the treatment of human insomnia and the promising aspects and limitations of these therapeutic interventions are discussed in this paper.
View details for DOI 10.1517/13543784.16.11.1785
View details for Web of Science ID 000251117000004
View details for PubMedID 17970638
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Acute effects of zolpidem on daytime alertness, psychomotor and physical performance
NEUROSCIENCE RESEARCH
2007; 59 (3): 309-313
Abstract
In a double-blind cross-over study, seven athletes received zolpidem (10mg) or placebo in two sessions over two nights. Residual effects on subsequent daytime functions were evaluated objectively by measuring psychomotor and physical performance using a combined test of finger dexterity, a simple discriminatory reaction test, critical flicker fusion test (CFF), vertical jump, and 50-m sprint, as well as subjectively, by visual analog scales. Zolpidem shortened self-estimated sleep latency and increased total sleep at nighttime. There was no change in alertness and fatigue scales on the following day in the zolpidem session, but realm of daytime well-being was slightly worsened. The CFF test showed significantly better results in the zolpidem group than in the placebo group. Zolpidem did not have effects in athletic evaluation. Zolpidem has a hypnotic activity without disturbing psychomotor and physical performance on the following day when given to healthy adults, suggesting zolpidem may be used in healthy athletes to adjust their extrinsic sleep disturbances and their consecutive psychomotor and physical impairments.
View details for DOI 10.1016/j.neures.2007.07.009
View details for Web of Science ID 000251023500010
View details for PubMedID 17825448
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Review of pathophysiology and clinical management of narcolepsy in dogs
VETERINARY RECORD
2007; 161 (11): 375-380
Abstract
Narcolepsy is a chronic sleep disorder that affects human beings and animals. Up to 17 breeds of dogs are affected sporadically, and familial forms occur in dobermanns, labrador retrievers and dachshunds. These dogs display characteristics strikingly similar to those of human narcolepsy, including cataplexy (a sudden loss of muscle tone in response to emotional stimulation) and a shorter sleep latency. It has recently been shown that the aetiology of both the familial form (receptor null mutation) and the sporadic form (loss of ligand production) of canine narcolepsy is associated with a deficit in hypocretin/orexin neurotransmission. Hypocretin deficiency can be detected by the measurement of hypocretin-1 in cerebrospinal fluid, and this could be used to diagnose hypocretin ligand deficient cases in clinical practice. Narcolepsy is neither progressive nor life-threatening, but the clinical signs persist throughout life, and lifelong treatment and care are required. This article reviews the recent progress in narcolepsy research in dogs, and describes the diagnosis and treatment of the disease.
View details for Web of Science ID 000249901800009
View details for PubMedID 17873267
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The hypothalamic peptidergic system, hypocretin/orexin and vigilance control
NEUROPEPTIDES
2007; 41 (3): 117-133
Abstract
Using forward and reverse genetics, the genes (hypocretin/orexin ligand and its receptor) involved in the pathogenesis of the sleep disorder, narcolepsy, in animals, have been identified. Mutations in hypocretin related-genes are extremely rare in humans, but hypocretin-ligand deficiency is found in most narcolepsy-cataplexy cases. Hypocretin deficiency in humans can be clinically detected by CSF hypocretin-1 measures, and undetectably low CSF hypocretin-1 is now included in the revised international diagnostic criteria of narcolepsy. Since hypocretin-ligand deficiency is the major pathophysiology in human narcolepsy, hypocretin replacements (using hypocretin agonists or gene therapy) are promising future therapeutic options. New insights into the roles of hypocretin system on sleep physiology have also rapidly increased. Hypocretins are involved in various fundamental hypothalamic functions such as feeding, energy homeostasis and neuroendocrine regulation. Hypocretin neurons project to most ascending arousal systems (including monoaminergic and cholinergic systems), and generally exhibit excitatory inputs. Together with the recent finding of the sleep promoting system in the hypothalamus (especially in the GABA/galanin ventrolateral preoptic area which exhibits inhibitory inputs to these ascending systems), the hypothalamus is now recognized as the most important brain site for the sleep switch, and other peptidergic systems may also participate in this regulation. Meanwhile, narcolepsy now appears to be a more complex condition than previously thought. The pathophysiology of the disease is involved in the abnormalities of sleep and various hypothalamic functions due to hypocretin deficiency, such as the changes in energy homeostasis, stress reactions and rewarding. Narcolepsy is therefore, an important model to study the link between sleep regulation and other fundamental hypothalamic functions.
View details for DOI 10.1016/j.npep.2007.01.003
View details for Web of Science ID 000247040700001
View details for PubMedID 17376528
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Clinical and neurobiological aspects of narcolepsy
SLEEP MEDICINE
2007; 8 (4): 373-399
Abstract
Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy and/or other dissociated manifestations of rapid eye movement (REM) sleep (hypnagogic hallucinations and sleep paralysis). Narcolepsy is currently treated with amphetamine-like central nervous system (CNS) stimulants (for EDS) and antidepressants (for cataplexy). Some other classes of compounds such as modafinil (a non-amphetamine wake-promoting compound for EDS) and gamma-hydroxybutyrate (GHB, a short-acting sedative for EDS/fragmented nighttime sleep and cataplexy) given at night are also employed. The major pathophysiology of human narcolepsy has been recently elucidated based on the discovery of narcolepsy genes in animals. Using forward (i.e., positional cloning in canine narcolepsy) and reverse (i.e., mouse gene knockout) genetics, the genes involved in the pathogenesis of narcolepsy (hypocretin/orexin ligand and its receptor) in animals have been identified. Hypocretins/orexins are novel hypothalamic neuropeptides also involved in various hypothalamic functions such as energy homeostasis and neuroendocrine functions. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in many narcolepsy-cataplexy cases. In this review, the clinical, pathophysiological and pharmacological aspects of narcolepsy are discussed.
View details for DOI 10.1016/j.sleep.2007.03.008
View details for Web of Science ID 000247230800007
View details for PubMedID 17470414
View details for PubMedCentralID PMC1978248
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Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy
JOURNAL OF PHYSIOLOGY-LONDON
2007; 581 (2): 649-663
Abstract
Recent population studies have identified important interrelationships between sleep duration and body weight regulation. The hypothalamic hypocretin/orexin neuropeptide system is able to influence each of these. Disruption of the hypocretin system, such as occurs in narcolepsy, leads to a disruption of sleep and is often associated with increased body mass index. We examined the potential interrelationship between the hypocretin system, metabolism and sleep by measuring locomotion, feeding, drinking, body temperature, sleep/wake and energy metabolism in a mouse model of narcolepsy (ataxin-ablation of hypocretin-expressing neurons). We found that locomotion, feeding, drinking and energy expenditure were significantly reduced in the narcoleptic mice. These mice also exhibited severe sleep/wake fragmentation. Upon awakening, transgenic and control mice displayed a similar rate of increase in locomotion and food/water intake with time. A lack of long wake episodes partially or entirely explains observed differences in overall locomotion, feeding and drinking in these transgenic mice. Like other parameters, energy expenditure also rose and fell depending on the sleep/wake status. Unlike other parameters, however, energy expenditure in control mice increased upon awakening at a greater rate than in the narcoleptic mice. We conclude that the profound sleep/wake fragmentation is a leading cause of the reduced locomotion, feeding, drinking and energy expenditure in the narcoleptic mice under unperturbed conditions. We also identify an intrinsic role of the hypocretin system in energy expenditure that may not be dependent on sleep/wake regulation, locomotion, or food intake. This investigation illustrates the need for coordinated study of multiple phenotypes in mouse models with altered sleep/wake patterns.
View details for DOI 10.1113/jphysiol.2007.129510
View details for Web of Science ID 000246756000022
View details for PubMedID 17379635
View details for PubMedCentralID PMC2075199
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Reduced expression of TACI, PENK and SOCS2 in Hcrtr-2 mutated narcoleptic dog brain
BMC NEUROSCIENCE
2007; 8
Abstract
Narcolepsy causes dramatic behavioral alterations in both humans and dogs, with excessive sleepiness and cataplexy triggered by emotional stimuli. Deficiencies in the hypocretin system are well established as the origin of the condition; both from studies in humans who lack the hypocretin ligand (HCRT) and in dogs with a mutation in hypocretin receptor 2 (HCRTR2). However, little is known about molecular alterations downstream of the hypocretin signals.By using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 [HCRTR-2-2] mutation), and their unaffected heterozygous siblings. We identified two neuropeptide precursor molecules, Tachykinin precursor 1 (TAC1) and Proenkephalin (PENK), that together with Suppressor of cytokine signaling 2 (SOCS2), showed reduced expression in narcoleptic brains. The difference was particularly pronounced in the amygdala, where mRNA levels of PENK were 6.2 fold lower in narcoleptic dogs than in heterozygous siblings, and TAC1 and SOCS2 showed 4.4 fold and 2.8 fold decrease in expression, respectively. The results obtained from microarray experiments were confirmed by real-time RT-PCR. Interestingly, it was previously shown that a single dose of amphetamine-like stimulants able to increase wakefulness in the dogs, also produce an increase in the expression of both TAC1 and PENK in mice.These results suggest that TAC1, PENK and SOCS2 might be intimately connected with the excessive daytime sleepiness not only in dogs, but also in other species, possibly including humans.
View details for DOI 10.1186/1471-2202-8-34
View details for Web of Science ID 000247020700001
View details for PubMedID 17521418
View details for PubMedCentralID PMC1885801
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Histamine H-3 receptor antagonists: From target identification to drug leads
BIOCHEMICAL PHARMACOLOGY
2007; 73 (8): 1084-1096
Abstract
The successful cloning and functional expression of the histamine H(3) receptor in the late 1990 s has greatly facilitated our efforts to identify small molecule, non-imidazole based compounds to permit the evaluation of H(3) antagonists in models of CNS disorders. High-throughput screening identified several series of lead compounds, including a series of imidazopyridines, which led to JNJ-6379490, a compound with high affinity for the human H(3) receptor. Analysis of structural features common to several series of non-imidazole H(3) receptor ligands resulted in a pharmacophore model. This model led to the design of JNJ-5207852, a diamine-based H(3) antagonist with good in vitro and in vivo efficacy but with an undesirable long half-life. However, further modifications of the template provided an understanding of the effect of structural modifications on pharmacokinetic properties, ultimately affording several additional series of compounds including JNJ-10181457, a compound with an improved pharmacokinetic profile. These compounds allowed in vivo pharmacological evaluation to show that H(3) antagonists promote wakefulness, but unlike modafinil and classical psychostimultants, they do not increase locomotor activity or produce any alteration of the EEG power spectral activity in rats. H(3) antagonists also increase extracellular acetylcholine and norepinephrine but not dopamine in rat frontal cortex and show efficacy in various models of learning-memory deficit. In addition, cFos immunoreactivity studies show H(3) antagonists activate neuronal cells in restricted rat brain regions in contrast to widespread activation after modafinil or amphetamine treatment. Therefore, H(3) antagonists are promising clinical candidates for the treatment of excessive day time sleepiness and/or cognitive disorders.
View details for DOI 10.1016/j.bcp.2006.10.031
View details for Web of Science ID 000245785300006
View details for PubMedID 17129577
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Neuropeptides as possible targets in sleep disorders: special emphasis on hypocretin-deficient narcolepsy.
CNS & neurological disorders drug targets
2007; 6 (1): 45-62
Abstract
Sleep disorders are disturbances of usual sleep patterns or behaviors caused by deregulation of neuronal synchronicity and of the balance of the neurotransmitter system involved in sleep regulation. Insomnia and hypersomnia are frequent sleep disorders, and these are most often treated pharmacologically with hypnotics and wake-promoting compounds. These compounds act on classical neurotransmitter systems, such as benzodiazepines on gamma amino butyric acid (GABA)(A) receptors, and amphetamine-like stimulants on monoaminergic terminals to modulate neurotransmission. In addition, acetylcholine, amino acids, lipids and proteins (cytokines) and peptides, are known to significantly modulate sleep, and thus, are possibly involved in the pathophysiology of some sleep disorders. Due to recent developments in molecular biological techniques, many neuropeptides have been newly identified, and some are found to significantly modulate sleep. Recent discoveries also include the finding that the impairment of hypocretin/orexin neurotransmission (a recently isolated hypothalamic neuropeptide and receptor system), is the major pathophysiology of narcolepsy with cataplexy. A hypocretin replacement therapy is anticipated to reverse the disease symptoms in humans. In this article, we will review the history of neuropeptide research, sleep modulatory effects of various neuropeptides, and the general strategies for the pharmacological therapeutics targeting the peptidergic systems by referring to hypocretin-deficient narcolepsy as an immediate example.
View details for PubMedID 17305553
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Neuropeptides as possible targets in sleep disorders
EXPERT OPINION ON THERAPEUTIC TARGETS
2007; 11 (1): 37-59
Abstract
Insomnia and hypersomnia are frequent sleep disorders, and they are most often treated pharmacologically with hypnotics and wake-promoting compounds. These compounds act on classical neurotransmitter systems, such as benzodiazepines on GABA-A receptors, and amfetamine-like stimulants on monoaminergic terminals to modulate neurotransmission. In addition, acetylcholine, amino acids, lipids and proteins (cytokines) and peptides, are known to significantly modulate sleep and are, therefore, possibly involved in the pathophysiology of some sleep disorders. Due to the recent developments of molecular biological techniques, many neuropeptides have been newly identified, and some are found to significantly modulate sleep. It was also discovered that the impairment of the hypocretin/orexin neurotransmission (a recently isolated hypothalamic neuropeptide system) is the major pathophysiology of narcolepsy, and hypocretin replacement therapy is anticipated to treat the disease in humans. In this article, the authors briefly review the history of neuropeptide research, followed by the sleep modulatory effects of various neuropeptides. Finally, general strategies for the pharmacological therapeutics targeting the peptidergic systems for sleep disorders are discussed.
View details for DOI 10.1517/14728222.11.1.37
View details for Web of Science ID 000243300800005
View details for PubMedID 17150033
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Cerebrospinal fluid histamine levels in rats across 24 hours and after various behavioral and pharmacological manipulations
21st Annual Meeting of the American-Professional-Sleep-Societies
AMER ACAD SLEEP MEDICINE. 2007: A60–A60
View details for Web of Science ID 000246224900176
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Narcolepsy: Pathophysiology and pharmacology
JOURNAL OF CLINICAL PSYCHIATRY
2007; 68: 9-15
Abstract
Narcolepsy, which affects 1 in 2000 people in the general population, is characterized by excessive daytime sleepiness (EDS), cataplexy, and other dissociated manifestations of rapid eye movement sleep (hypnagogic hallucinations and sleep paralysis). The disease is currently treated with amphetamine-like central nervous system stimulants (for EDS) and antidepressants (for cataplexy). Some compounds from other classes, such as modafinil (a non-amphetamine wake-promoting compound for EDS) and sodium oxybate (a short-acting sedative for EDS and cataplexy, administered at night), are also employed. The major pathophysiology of human narcolepsy has recently been revealed by the extension of discoveries of narcolepsy genes in animal models: hypocretin/orexin ligand deficiency has been shown in about 90% of human narcolepsy-cataplexy. This finding led directly to the development of new diagnostic tests (i.e., cerebrospinal fluid hypocretin measures). Hypocretin replacement is also likely to be a new therapeutic option for hypocretin-deficient narcolepsy, but is still not available in humans. In this review, the pharmacologic and pathophysiologic aspects of narcolepsy are discussed.
View details for Web of Science ID 000251940000003
View details for PubMedID 18078360
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Addiction and arousal: Alternative roles of hypothalamic peptides
JOURNAL OF NEUROSCIENCE
2006; 26 (41): 10372-10375
Abstract
The importance of the lateral hypothalamus in the regulation of reward and motivation has long been recognized. However, the neuronal network involved in such a hypothalamic regulation of reward remains essentially unknown. Recently, hypocretin-containing neurons, a group of hypothalamic neurons known to be associated with the stability of arousal, have emerged as important structures in the control of brain reward function. This review summarizes a Mini-Symposium presented at the 2006 Annual Meeting of the Society for Neuroscience.
View details for DOI 10.1523/JNEUROSCI.3118-06.2006
View details for Web of Science ID 000241192800008
View details for PubMedID 17035520
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Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models
PEPTIDES
2006; 27 (9): 2326-2331
Abstract
Recent studies in human and animal models of narcolepsy have suggested that obesity in narcolepsy may be due to deficiency of hypocretin signaling, and is also under the influence of environmental factors and the genetic background. In the current study, using two hypocretin/orexin deficient narcoleptic mouse models (i.e. preproorexin knockout (KO) and orexin/ataxin-3 transgenic (TG) mice) with cross-sectional assessments, we have further analyzed factors affecting obesity. We found that both KO and TG narcoleptic mice with mixed genetic backgrounds (N4-5, 93.75-96.88% genetic composition of C57BL/6) tended to be heavier than wild type (WT) mice of 100-200 days old. The body weight of heterozygous mice was intermediate between those of KO and WT mice. Obesity was more prominent in females in both KO and TG narcoleptic mice and was associated with higher serum leptin levels, suggesting a partial leptin resistance. Obesity is less prominent in the congenic TG narcoleptic mice, but is still evident in females. Our results confirmed that hypocretin/orexin ligand deficiency is one of the critical factors for the obese tendency in narcolepsy. However, multiple factors are also likely to affect this phenotype, and a sex difference specific alteration of leptin-hypocretin signaling may be involved.
View details for DOI 10.1016/j.peptides.2006.03.011
View details for Web of Science ID 000240379800037
View details for PubMedID 16626839
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CSF versus serum leptin in narcolepsy: Is there an effect of hypocretin deficiency?
SLEEP
2006; 29 (8): 1017-1024
Abstract
To determine if hypocretin deficiency is associated with abnormally low serum leptin levels, a putative cause of increased body mass index in narcoleptics.Cross-sectional controlled study.Three hundred seventy subjects, including 111 healthy controls, 93 narcoleptic subjects with hypocretin deficiency (cerebrospinal fluid [CSF] hypocretin-1 levels < 110 pg/mL), 72 narcoleptic subjects with normal hypocretin levels, and 89 subjects with other sleep disordersAfter completing the Stanford Sleepiness Inventory, participants underwent spinal taps and blood sampling for measurement of CSF leptin and hypocretin-1 levels, HLA DQB1*0602 phenotyping, and serum leptin and C-reactive protein levels.Serum leptin levels were similar in narcoleptic subjects, whether hypocretin-deficient (13.2 +/- 1.7 ng/mL, mean +/- SEM) or not (13.0 +/- 1.8 ng/mL), controls (10.1 +/- 1.1 ng/mL) and subjects with other sleep disorders (11.5 +/- 1.6 ng/mL). Similarly, the CSF leptin levels and the CSF: serum leptin ratios (an indicator of brain leptin uptake) were not different between groups. Serum and CSF leptin levels were higher in women and in subjects with higher body mass indexes. Leptin brain uptake decreased in women, in the aged, and in more-obese subjects. In contrast with a presumed inhibitory effect of leptin on hypocretin-containing cells, CSF leptin levels tended to correlate positively with CSF hypocretin-1 levels. C-reactive protein was higher (4.2 +/- 0.9 mg/L) in narcoleptic subjects with hypocretin deficiency than in controls (1.4 +/- 0.3 mg/L, p = .0055), a difference still significant after adjustment on confounding factors.Our data do not support a role for leptin in mediating increased body mass index in narcolepsy. A moderate but selective increase in C-reactive protein in hypocretin-1 deficient subjects should prompt research on inflammation in narcolepsy.
View details for Web of Science ID 000240046400004
View details for PubMedID 16944669
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CSF orexin A concentrations and expressions of the orexin-1 receptor in rat hippocampus after cardiac arrest
NEUROPEPTIDES
2006; 40 (4): 245-250
Abstract
Orexins/hypocretins are neuropeptides that have various physiological effects, including the regulation of feeding behavior, neuroendocrine functions and sleep-wake cycles. Recent studies have suggested that the orexin system may also be involved in brain ischemic reactions. It is also known that changes in sleep patterns, energy homeostasis and neuroendocrine functions are often occur in neurological conditions associated brain ischemia. In the current study, we investigated the time-dependent changes in cerebrospinal fluid (CSF) orexin-A concentration and the expression of the orexin-1 receptor (OX1R) in the rat hippocampus after global ischemia-reperfusion (5 min cardiopulmonary arrest), which is known to induce delayed cell death in the CA1 region of the hippocampus. The CSF orexin-A concentration was elevated transiently at 24 h after ischemia. On days 2 and 4 after ischemia, CSF orexin concentrations were significantly reduced relative to the baseline, and returned to the baseline level by day 7. These changes were correlated with increased expression of OX1R in the CA1 on days 1 and 2 post-ischemia. These results suggest that dynamics of orexin signaling observed may have functional roles for neuronal damage associated with transient ischemia.
View details for DOI 10.1016/j.npep.2006.06.003
View details for Web of Science ID 000240969600002
View details for PubMedID 16930690
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The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions
TRENDS IN PHARMACOLOGICAL SCIENCES
2006; 27 (7): 368-374
Abstract
Narcolepsy is characterized by excessive daytime sleepiness, cataplexy and other manifestations of dissociated rapid eye movement sleep. Narcolepsy is typically treated with amphetamine-like stimulants (sleepiness) and antidepressants (cataplexy). Newer compounds, such as modafinil (non-amphetamine wake-promoting compound for excessive daytime sleepiness) and sodium oxybate (short-acting sedative for fragmented nighttime sleep, cataplexy, excessive daytime sleepiness), are increasingly used. Recent discoveries indicate that the major pathophysiology of human narcolepsy is the loss of lateral hypothalamic neurons that produce the neuropeptide hypocretin (orexin). Approximately 90% of people diagnosed as having narcolepsy with cataplexy are hypocretin ligand deficient. This has led to the development of new diagnostic tests (cerebrospinal fluid hypocretin-1 measurements). Hypocretin receptor agonists are likely to be ideal therapeutic options for hypocretin-deficient narcolepsy but such compounds are still not available in humans.
View details for DOI 10.1016/j.tips.2006.05.006
View details for Web of Science ID 000239368900005
View details for PubMedID 16766052
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Expression pattern of FOS in orexin neurons during sleep induced by an adenosine A(2A) receptor agonist
BEHAVIOURAL BRAIN RESEARCH
2006; 170 (2): 277-286
Abstract
The present study examined the expression pattern of FOS in the hypothalamic peptide neurons during the sleep-dominant state induced by an adenosine A2A receptor agonist. The control rats, those that received the microdialysis-perfusion of their ventral striatum with artificial cerebrospinal fluid in the dark-active phase, spent 24% of the 90-min period prior to sacrifice in non-rapid eye movement (non-REM) sleep and 2.3% of that in REM sleep. These rats exhibited FOS, a transcription factor, in 21% of their orexin neurons and in 1.0% of their melanin-concentrating hormone (MCH) neurons in the perifornical/lateral hypothalamic areas. However, the rats perfused with 50 microM CGS21680, an adenosine A2A receptor agonist, spent 60% of the 90-min period prior to sacrifice in non-REM sleep and 11% of that in REM sleep. These rats exhibited FOS in 1.7% of their orexin neurons and FOS in 0.5% of their MCH neurons. When the sleep-dominant state was disturbed by mild stimulation and the rats were kept in the sleepy state by treatment with a sleep-inducing dose of CGS21680, the rats exhibited FOS in 13.3% of their orexin neurons, which percentage was about half of that for the control rats. These results suggest that the sleep-promoting process induced by this adenosine A2A receptor agonist was associated with a decline in the activity of orexin neurons. MCH neurons are not likely to change their activities during this sleep-promoting process.
View details for DOI 10.1016/j.bbr.2006.03.010
View details for Web of Science ID 000238179500013
View details for PubMedID 16621044
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An activation of parvocellular oxytocinergic neurons in the paraventricular nucleus in oxytocin-induced yawning and penile erection
NEUROSCIENCE RESEARCH
2006; 54 (4): 269-275
Abstract
Intracerebroventricular (ICV) or PVN local injections of oxytocin induce yawning and penile erection, for which a positive feedback mechanism for the PVN oxytocinergic activation is suggested, but this had not been directly substantiated in vivo. We have assessed the behavioral effects and activity of oxytocinergic neurons with double-staining for c-Fos and oxytocin in the PVN after ICV administration of oxytocin in adult male rats. ICV oxytocin injections (50 and 200 ng) dose-dependently induced yawning and penile erection and significantly increased the percentage of c-Fos positive oxytocin neurons in the medial, dorsal and lateral parvocellular subdivision of the PVN. However, increases in the magnocellular portion were not significant. We also found that lithium chloride (LiCl, 0.5 and l.0 mEq), a compound known to activate oxytocinergic neurons, also significantly increased the percentage of c-Fos positive oxytocin neurons in all PVN portions. However, LiCl did not induce yawning and penile erection, but counteracted the oxytocin-induced yawning and penile erection. These results suggest that if the activation of oxytocinergic neurons in the PVN is important for mediating oxytocin-induced yawning and penile erection, a selective activation of parvocellular oxytocinergic neurons in the PVN is likely to be involved.
View details for DOI 10.1016/j.neures.2005.12.005
View details for Web of Science ID 000236539200004
View details for PubMedID 16427151
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Diurnal variation in CSF Orexin-A in healthy male subjects
SLEEP
2006; 29 (3): 295-297
Abstract
Orexin-A is hypothesized to promote wakefulness, and we examined whether cerebrospinal fluid (CSF) orexin-A levels are higher during the waking period in man.Within-subjects, repeated-measures design with balanced ordering of sampling at approximately 5 AM and 5 PM.Eight healthy young males. MESUREMENTS: CSF orexin-A levels and standard polysomnography.Orexin-A levels during the sleep period were 4% higher than during the waking period (314.9 pg/ml versus 302.8 pg/ml, p < 0.03). Sleep period orexin-A levels were negatively correlated with REM sleep as a percentage of total sleep time (p < 0.05). The day and night levels of orexin-A were strongly correlated within subjects (r = 0.97; p < 0.0001) even though the samples were collected 1-2 weeks apart.Orexin-A levels in lumbar CSF are slightly higher at 5 AM than at 5 PM. Because orexin release is thought to be highest during the waking period, this observation was unexpected and may reflect a long delay between the release of orexin and its appearance in lumbar CSF. Orexin-A levels vary moderately between subjects, but are quite consistent within the same subject. Thus, for the diagnostic evaluation of narcolepsy, the time of CSF collection should have little impact.
View details for Web of Science ID 000240123600004
View details for PubMedID 16553014
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Conditions of primary excessive daytime sleepiness
NEUROLOGIC CLINICS
2005; 23 (4): 1025-?
Abstract
Excessive daytime somnolence is a prevalent problem in medical practice and in society. It exacts a great toll in quality of life, personal and public safety, and productivity. The causes of EDS are myriad, and careful evaluation is needed to determine the cause in each case. Although much progress has been made in discovering the pathophysiology of narcolepsy, much more remains to be understood, and far less is known about other primary conditions of EDS. Several methods have been developed to assess EDS, although each of them has limitations. Treatment is available for the great majority of cases.
View details for DOI 10.1016/j.ncl.2005.08.002
View details for Web of Science ID 000233258100006
View details for PubMedID 16243614
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[An old and new focal symptom, hypothalamus and hypersomnia, orexin system and narcolepsy].
Rinsho shinkeigaku = Clinical neurology
2005; 45 (11): 824-827
View details for PubMedID 16447736
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Enhanced antinociception by intracerebroventricularly administered orexin A in histamine H1 or H2 receptor gene knockout mice
PAIN
2005; 118 (1-2): 254-262
Abstract
Orexins are neuropeptides that are mostly expressed in the posterior and lateral hypothalamus, and related to the central control of appetite, arousal, and antinociception. Orexin neurons projected to the tuberomammillary nucleus and orexins may release histamine from the histamine neurons in this nucleus. Histamine is known to cause hypernociception. The roles of histamine H1 and H2 receptors in the orexin A-induced antinociception, however, have not been clarified yet. Here we studied the effects of histamine H1 and H2 receptors on orexin A-produced antinociception using histamine receptor knockout mice in four assays of nociception; the hot-plate, the tail-flick, the tail-pressure and the capsaicin tests. Furthermore we studied effects of histamine H1 and H2 receptor antagonists on orexin A-produced antinociception in C57BL/6 mice. The antinociceptive effects of i.c.v. orexin A were greater in histamine H1 receptor or H2 receptor knockout mice than in the wild-type mice in all four assays of pain. Furthermore, treatment of C57BL/6 mice with a combination of i.c.v. orexin A and d-chlorpheniramine (a histamine H1 receptor antagonist) or cimetidine (a histamine H2 receptor antagonist) showed a greater antinociception than i.c.v. orexin A alone in all four assays. These findings suggest the possibility that orexin A may activate H1 and H2 receptors in the supraspinal levels through the release of histamine from neurons, which might attenuate the antinociceptive effects of orexin A. Thus, the blocking of the histamine H1 or H2 receptor may produce antinociception and enhance the orexin A-induced antinociception.
View details for DOI 10.1016/j.pain.2005.08.024
View details for Web of Science ID 000233281800032
View details for PubMedID 16202530
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CSF hypocretin-1/orexin-A concentrations in patients with subarachnoid hemorrhage (SAH)
PEPTIDES
2005; 26 (11): 2339-2343
Abstract
The aim of this study was to examine the role of the hypothalamic hypocretin/orexin system in complications of delayed ischemic neuronal deficit (DIND) resulting from symptomatic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH). CSF hypocretin-1/orexin-A levels were measured in 15 SAH patients. DIND complications occurred in seven patients with symptomatic vasospasm. Hypocretin-1/orexin-A levels were low in SAH patients during the 10 days following the SAH event. CSF hypocretin-1/orexin-A levels were lower in patients with DIND complications than in those who did not develop DIND. A significant transient decline in CSF hypocretin-1/orexin-A levels was also observed at the onset of DIND in all patients with symptomatic vasospasm. The reduced hypocretin/orexin production observed in SAH patients may reflect reduced brain function due to the decrease in cerebral blood flow. These results, taken together with recent experimental findings in rats that indicate hypocretin receptor 1 (orexin 1 receptor) mRNA and protein are elevated following middle cerebral artery occlusion, suggest that a reduction in hypocretin/orexin production in SAH and DIND patients is associated with alterations in brain hypocretin/orexin signaling in response to ischemia.
View details for DOI 10.1016/j.peptides.2005.04.004
View details for Web of Science ID 000233373100040
View details for PubMedID 15893406
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Hypersomnolence and increased REM sleep with low cerebrospinal fluid hypocretin level in a patient after removal of craniopharyngioma
SLEEP MEDICINE
2005; 6 (6): 567-569
Abstract
Here we report a hypersomnolent girl with extensive hypothalamic damage after removal of a craniopharyngioma. The presence of a short sleep latency, sleep onset REM periods during a multiple sleep latency test (MSLT) and negative HLA DQB1*0602 typing suggested a diagnosis of symptomatic narcolepsy. Low cerebrospinal fluid hypocretin-1 level indicated destruction of hypocretin-producing neurons in the hypothalamus. An increased amount of REM sleep and a lack of REM sleep cyclicity documented by all-night polysomnography were different findings from previous reports of hypocretin-deficient idiopathic symptomatic narcolepsy. A more global hypothalamic lesion demonstrated by brain magnetic resonance imaging (MRI) after surgery seemed to cause marked disinhibition of REM sleep as well as hypersomnolence in this patient.
View details for DOI 10.1016/j.sleep.2005.04.002
View details for Web of Science ID 000233577000014
View details for PubMedID 16084764
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Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system
SLEEP MEDICINE REVIEWS
2005; 9 (4): 269-310
Abstract
Human narcolepsy is a chronic sleep disorder affecting 1:2000 individuals. The disease is characterized by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep, such as sleep paralysis and hypnagogic hallucinations. Recently, it was discovered that the pathophysiology of (idiopathic) narcolepsy-cataplexy is linked to hypocretin ligand deficiency in the brain and cerebrospinal fluid (CSF), as well as the positivity of the human leukocyte antigen (HLA) DR2/DQ6 (DQB1*0602). The symptoms of narcolepsy can also occur during the course of other neurological conditions (i.e. symptomatic narcolepsy). We define symptomatic narcolepsy as those cases that meet the International Sleep Disorders Narcolepsy Criteria, and which are also associated with a significant underlying neurological disorder that accounts for excessive daytime sleepiness (EDS) and temporal associations. To date, we have counted 116 symptomatic cases of narcolepsy reported in literature. As, several authors previously reported, inherited disorders (n=38), tumors (n=33), and head trauma (n=19) are the three most frequent causes for symptomatic narcolepsy. Of the 116 cases, 10 are associated with multiple sclerosis, one case of acute disseminated encephalomyelitis, and relatively rare cases were reported with vascular disorders (n=6), encephalitis (n=4) and degeneration (n=1), and hererodegenerative disorder (three cases in a family). EDS without cataplexy or any REM sleep abnormalities is also often associated with these neurological conditions, and defined as symptomatic cases of EDS. Although it is difficult to rule out the comorbidity of idiopathic narcolepsy in some cases, review of the literature reveals numerous unquestionable cases of symptomatic narcolepsy. These include cases with HLA negative and/or late onset, and cases in which the occurrences of the narcoleptic symptoms are parallel with the rise and fall of the causative disease. A review of these cases (especially those with brain tumors), illustrates a clear picture that the hypothalamus is most often involved. Several cases of symptomatic cataplexy (without EDS) were also reported and in contrast, these cases appear to be often associated with non-hypothalamic structures. CSF hypocretin-1 measurement were also carried out in a limited number of symptomatic cases of narcolepsy/EDS, including narcolepsy/EDS associated with tumors (n=5), head trauma (n=3), vascular disorders (n=5), encephalopathies (n=3), degeneration (n=30), demyelinating disorder (n=7), genetic/congenital disorders (n=11) and others (n=2). Reduced CSF hypocretin-1 levels were seen in most symptomatic narcolepsy cases of EDS with various etiologies and EDS in these cases is sometimes reversible with an improvement of the causative neurological disorder and an improvement of the hypocretin status. It is also noted that some symptomatic EDS cases (with Parkinson diseases and the thalamic infarction) appeared, but they are not linked with hypocretin ligand deficiency. In contrast to idiopathic narcolepsy cases, an occurrence of cataplexy is not tightly associated with hypocretin ligand deficiency in symptomatic cases. Since CSF hypocretin measures are still experimental, cases with sleep abnormalities/cataplexy are habitually selected for CSF hypocretin measures. Therefore, it is still not known whether all or a large majority of cases with low CSF hypocretin-1 levels with CNS interventions, exhibit EDS/cataplexy. It appears that further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiological mechanisms for the occurrence of EDS and cataplexy.
View details for DOI 10.1016/j.smrv.2005.03.004
View details for Web of Science ID 000231170000005
View details for PubMedID 16006155
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Polymorphisms within the canine MLPH gene are associated with dilute coat color in dogs
BMC GENETICS
2005; 6
Abstract
Pinschers and other dogs with coat color dilution show a characteristic pigmentation phenotype. The fur colors are a lighter shade, e.g. silvery grey (blue) instead of black and a sandy color (Isabella fawn) instead of red or brown. In some dogs the coat color dilution is sometimes accompanied by hair loss and recurrent skin inflammation, the so called color dilution alopecia (CDA) or black hair follicular dysplasia (BHFD). In humans and mice a comparable pigmentation phenotype without any documented hair loss is caused by mutations within the melanophilin gene (MLPH).We sequenced the canine MLPH gene and performed a mutation analysis of the MLPH exons in 6 Doberman Pinschers and 5 German Pinschers. A total of 48 sequence variations was identified within and between the breeds. Three families of dogs showed co-segregation for at least one polymorphism in an MLPH exon and the dilute phenotype. No single polymorphism was identified in the coding sequences or at splice sites that is likely to be causative for the dilute phenotype of all dogs examined. In 18 German Pinschers a mutation in exon 7 (R199H) was consistently associated with the dilute phenotype. However, as this mutation was present in homozygous state in four dogs of other breeds with wildtype pigmentation, it seems unlikely that this mutation is truly causative for coat color dilution. In Doberman Pinschers as well as in Large Munsterlanders with BHFD, a set of single nucleotide polymorphisms (SNPs) around exon 2 was identified that show a highly significant association to the dilute phenotype.This study provides evidence that coat color dilution is caused by one or more mutations within or near the MLPH gene in several dog breeds. The data on polymorphisms that are strongly associated with the dilute phenotype will allow the genetic testing of Pinschers to facilitate the breeding of dogs with defined coat colors and to select against Large Munsterlanders carrying BHFD.
View details for DOI 10.1186/1471-2156-6-34
View details for Web of Science ID 000231069500001
View details for PubMedID 15960853
View details for PubMedCentralID PMC1183202
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Emerging therapies in narcolepsy-cataplexy
SLEEP
2005; 28 (6): 754-763
Abstract
In the past, narcolepsy was primarily treated using amphetamine-like stimulants and tricyclic antidepressants. Newer and novel agents, such as the wake-promoting compound modafinil and more selective reuptake inhibitors targeting the adrenergic, dopaminergic, and/or serotoninergic reuptake sites (ie, venlafaxine, atomoxetine) are better-tolerated available alternatives. The development of these agents, together with sodium oxybate (a slow-wave sleep-enhancing agent that consolidates nocturnal sleep, reduces cataplexy, and improves sleepiness), has led to improved functioning and quality of life for many patients with the disorder. However, these treatments are all symptomatically based and do not target hypocretin, a major neurotransmitter involved in the pathophysiology of narcolepsy. In this review, we discuss emerging therapies in the area of narcolepsy. These include novel antidepressant or anticataplectic, wake-promoting, and hypnotic compounds. We also report on novel strategies designed to compensate for hypocretin deficiency and on the use of immunosupression at the time of narcolepsy onset.
View details for Web of Science ID 000229900500014
View details for PubMedID 16477963
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Enhanced antinociception by intracerebroventricularly and intrathecally-administered orexin A and B (hypocretin-1 and-2) in mice
PEPTIDES
2005; 26 (5): 767-777
Abstract
Orexins are neuropeptides located exclusively in neurons of the lateral hypothalamic area, which send projections to most monoaminergic nuclei, such as noradrenergic locus coeruleus, dopaminergic ventral tegmental areas, and histaminergic tuberomammillary nuclei. The present work was carried out to examine the role of orexins in nociception in mice. C57BL/6 mice were administered with orexin A and B intracerebroventricularly (i.c.v.), intrathecally (i.t.) and subcutaneously (s.c.) to reveal the sites of action of these peptides and to examine the pain thresholds using four kinds of nociceptive tasks. Orexins showed antinociceptive effects in all four types of assays for thermal (hot-plate, tail-flick, paw-withdrawal), mechanical (tail-pressure), chemical (formalin, capsaicin and abdominal stretch) nociceptions and nociceptin-induced behavioral responses, when administered i.c.v. or i.t., whereas the s.c. administration was ineffective. The antinociceptive effects of orexin A were more remarkable than those of orexin B. The i.c.v. administration of orexin A was as effective as, or more potent than the i.t. administration. The effects of orexin A were completely blocked by adenosine type 1 receptor antagonists, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and theophylline, but not by naloxone, suggesting a possible involvement of the adenosine-containing neurons and/or the adenosine pathway in these orexin actions. The i.c.v. administration of nociceptin had no significant effects on orexin expression in the brain and spinal cord. The present findings suggest that orexins have an antinociceptive role in at least four different types of pains, probably acting on both the brain and spinal cord.
View details for DOI 10.1016/j.peptides.2005.01.001
View details for Web of Science ID 000228594600009
View details for PubMedID 15808907
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Hypocretin deficiency in Prader-Willi syndrome
EUROPEAN JOURNAL OF NEUROLOGY
2005; 12 (1): 70-72
Abstract
Four patients with clinically and genetically confirmed Prader-Willi syndrome (PWS) underwent nocturnal polysomnograpy (PSG), multiple sleep latency test (MSLT), human leukocyte antigens (HLA) typing and estimation of cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) level to investigate if a role of hypothalamic dysfunction and sleep disturbance might be functionally connected through the hypocretin (orexin) system. In all four patients physical examination confirmed extreme obesity (increasing with age) with dysmorphogenetic features. Excessive daytime sleepiness (EDS) was manifested in only two subjects without any imperative feature. None of the patients under study suffered from cataplexy. Nocturnal PSG revealed fragmented sleep with low efficiency, the hypopnea and apnea indexes increasing from borderline up to very high values in direct proportion to the patients' age. MSLT latency was shortened in two patients with clinically expressed EDS, only one sleep onset rapid eye movements (REM) period (SOREM) was found. HLA typing showed DQB1*0602 positivity in two patients; the further two were negative. Mean value of CSF Hcrt-1 in the patients group was down to 164 +/- 46.8 pg/ml (in comparison with 265.8 +/- 48.8 pg/ml in 10 young healthy subjects, P=0.02). The deficiency of CSF Hcrt-1 level correlated in PWS patients with their EDS severity.
View details for Web of Science ID 000225955700012
View details for PubMedID 15613151
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The anticataplectic effect of milnacipran, a new serotonin noradrenaline reuptake inhibitor, on human and canine narcolepsy
19th Annual Meeting of the Associated-Professional-Sleep-Societies
AMER ACAD SLEEP MEDICINE. 2005: A215–A216
View details for Web of Science ID 000228906101150
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Hypersomnia and low cerebrospinal fluid hypocretin levels in acute disseminated encephalomyelitis
PEDIATRIC NEUROLOGY
2004; 31 (5): 367-370
Abstract
A 7-year-old Japanese female diagnosed as having acute disseminated encephalomyelitis presented seizures, visual symptoms, and hypersomnia with bilateral lesions in the white matter, basal ganglia, and hypothalamus. Her clinical findings and demonstrated lesions in neuroimages were similar to those of Von Economo's encephalitis lethargica. Her hypocretin, the hypothalamic neuropeptide controlling sleep-awake cycle, was significantly low in the cerebrospinal fluid (146 pg/mL) on admission. Successive measures resulted in the gradual recovery of cerebrospinal fluid hypocretin to the normal range (263 pg/mL) as her excessive daytime sleepiness was reduced. Decreased hypothalamic hypocretin neurotransmission may be involved in this symptomatic case of hypersomnia associated with acute disseminated encephalomyelitis.
View details for Web of Science ID 000225313400012
View details for PubMedID 15519122
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Narcolepsy and syndromes of primary excessive daytime somnolence
SEMINARS IN NEUROLOGY
2004; 24 (3): 271-282
Abstract
Excessive daytime sleepiness (EDS) or somnolence is common in our patients and in society in general. The most common cause of EDS is "voluntary" sleep restriction. Other common causes include sleep-fragmenting disorders such as the obstructive sleep apnea syndrome. Somewhat less familiar to the clinician are EDS conditions arising from central nervous system dysfunction. Of these so-called primary disorders of somnolence, narcolepsy is the most well known and extensively studied, yet often misunderstood and misdiagnosed. Idiopathic hypersomnia, the recurrent hypersomnias, and EDS associated with nervous system disorders also must be well-understood to provide appropriate evaluation and management of the patient with EDS. This review summarizes the distinguishing features of these clinical syndromes of primary EDS. A brief overview of the pharmacological management of primary EDS is included. Finally, in view of the tremendous advances that have occurred in the past few years in our understanding of the pathophysiology of canine and human narcolepsy, we also highlight these discoveries.
View details for Web of Science ID 000224248200007
View details for PubMedID 15449220
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The diurnal rhythm of hypocretin in young and old F344 rats
SLEEP
2004; 27 (5): 851-856
Abstract
Hypocretins (HCRT-1 and HCRT-2), also known as orexins, are neuropeptides localized in neurons surrounding the perifornical region of the posterior hypothalamus. These neurons project to major arousal centers in the brain and are implicated in regulating wakefulness. In young rats and monkeys, levels of HCRT-1 are highest at the end of the wake-active period and lowest toward the end of the sleep period. However, the effects of age on the diurnal rhythm of HCRT-1 are not known.To provide such data, cerebrospinal fluid (CSF) was collected from the cisterna magna of young (2-month-old, n = 9), middle-aged (12 months, n = 10), and old (24 months, n = 10) F344 rats at 4-hour intervals, (beginning at zeitgeber [ZT]0, lights on). CSF was collected once from each rat every 4 days at 1 ZT point. After collecting the CSF at all of the time points, the rats were kept awake by gentle handling for 8 hours (ZT 0-ZT8), and the CSF was collected again at the end of the sleep-deprivation procedure. HCRT-1 levels in the CSF were determined by radioimmunoassayBasic neuroscience research lab.Old rats had significantly less HCRT-1 in the CSF versus young and middle-aged rats (P < .002) during the lights-on and lights-off periods and over the 24-hour period. In old rats, significantly low levels of HCRT-1 were evident at the end of the lights-off period (predominantly wake-active period). The old rats continued to have less HCRT-1 even after 8 hours of prolonged waking. Northern blot analysis did not show a difference in pre-proHCRT mRNA between age groups.In old rats there is a 10% decline in CSF HCRT-1 over the 24-hour period. Functionally, if there is less HCRT-1, which our findings indicated, and there is also a decline in HCRT receptor mRNA, as has been previously found, then the overall consequence would be diminished action of HCRT at target sites. This would diminish the waking drive, which in the elderly could contribute to the increased tendency to fall asleep during the normal wake period.
View details for Web of Science ID 000223451400006
View details for PubMedID 15453542
View details for PubMedCentralID PMC1201560
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Mistaken diagnosis of psychogenic gait disorder in a man with status cataplecticus ("limp man syndrome")
MOVEMENT DISORDERS
2004; 19 (7): 838-840
Abstract
We report on a 45-year-old man with a history of multiple psychiatric admissions for a gait disorder and episodic weakness thought to be psychogenic who was subsequently diagnosed with status cataplecticus due to narcolepsy. The gait difficulties resolved with venlafaxine. This case demonstrates that status cataplecticus can be misdiagnosed as a psychogenic gait disorder.
View details for DOI 10.1002/mds.20078
View details for Web of Science ID 000222855000018
View details for PubMedID 15254948
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Lesions of the suprachiasmatic nucleus eliminate the daily rhythm of hypocretin-1 release
SLEEP
2004; 27 (4): 619-627
Abstract
Hypocretins (orexins) are involved in the sleep disorder narcolepsy. While hypocretin-1 has a daily oscillation, little is known regarding the relative contribution of circadian and homeostatic components on hypocretin release. The effect of lesions of the suprachiasmatic nucleus (SCN) on hypocretin-1 in the cerebrospinal fluid (CSF) was examined.SCN-ablated (SCNx) and sham-operated control rats were implanted with activity-temperature transmitters. Animals were housed individually under 1 of 3 lighting conditions: 12-hour:12-hour light:dark cycle (LD), constant light (LL), and constant darkness (DD). Lesions were verified histologically and shown not to affect hypocretin-containing cells. Hypocretin-1 concentrations in the CSF were determined every 4 hours using radioimmunoassays.Control animals displayed robust circadian (LL, DD) and diurnal (LD) fluctuations in CSF hypocretin-1, locomotor activity, and temperature. Peak CSF hypocretin-1 was at the end of the active period. Activity, temperature, and CSF hypocretin-1 were arrhythmic in SCNx animals in LL and DD. In LD, a weak but significant fluctuation in activity and temperature but not CSF hypocretin-1 was observed in SCNx animals. We also explored correlations between CSF hypocretin-1, CSF corticosterone, and locomotor activity occurring prior to CSF sampling in arrhythmic SCNx rats under constant conditions. Significant correlations between hypocretin-1 and activity were observed both across and within animals, suggesting that interindividual and time-of-the-day differences in activity have significant effects on hypocretin release in arrhythmic animals. No correlation was found between CSF hypocretin-1 and corticosterone.Hypocretin-1 release is under SCN control. Locomotor activity influences the activity of the hypocretin neurons.
View details for Web of Science ID 000223169300007
View details for PubMedID 15282996
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The roles of midbrain and diencephalic dopamine cell groups in the regulation of cataplexy in narcoleptic Dobermans
NEUROBIOLOGY OF DISEASE
2004; 16 (1): 274-282
Abstract
Cataplexy, an emotion-triggered sudden loss of muscle tone specific to narcolepsy, is tightly associated with hypocretin deficiency. Using hypocretin receptor 2 gene (hcrtr 2)-mutated narcoleptic Dobermans, we have previously demonstrated that altered dopamine (DA) D(2/3) receptor mechanisms in mesencephalic DA nuclei are important for the induction of cataplexy. In the current study, we also found that the administration of D(2/3) agonists into diencephalic dopaminergic cell groups, including the area dorsal to the ventral tegmental area (DRVTA) and the periventricular gray (PVG) matter of the caudal thalamus (corresponding to area A11), significantly aggravated cataplexy in hcrtr 2-mutated narcoleptic Dobermans. A D(1) agonist and antagonist and a DA uptake inhibitor perfused into the DRVTA had no effect on cataplexy, suggesting an involvement of D(2/3) receptors located on DA cell bodies (i.e., autoreceptors) for the regulation of cataplexy. Because the A11 cell group projects to the spinal ventral horn, the A11 D(2/3) receptive mechanisms may directly modulate the activity of spinal motoneurons and modulate cataplexy.
View details for DOI 10.1016/j.nbd.2004.02.008
View details for Web of Science ID 000221365300029
View details for PubMedID 15207284
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FOS expression in orexin neurons following muscimol perfusion of preoptic area
NEUROREPORT
2004; 15 (7): 1127-1131
Abstract
Unilateral microdialysis-perfusion of the preoptic area with 50 microM muscimol decreased the sleep period of rats to less than 3% of the baseline value over a 90 min period before death (p = 0.018 by Wilcoxon signed-rank test). These rats showed the expression of FOS in 36% of the orexin neurons located in the perifornical/lateral hypothalamic areas on the side ipsilateral to the perfusion site, but in only 3% of the orexin neurons on the side contralateral to it (p = 0.018 by Wilcoxon signed-rank test). These results suggest that subpopulations of the preoptic neurons give an inhibitory tone to the activities of the orexin neurons in the perifornical/lateral hypothalamic areas.
View details for DOI 10.1097/01.wnr.0000125775.20021.6b
View details for Web of Science ID 000225140400009
View details for PubMedID 15129159
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Narcolepsy caused by acute disseminated encephalomyelitis
ARCHIVES OF NEUROLOGY
2004; 61 (5): 758-760
Abstract
Narcolepsy with cataplexy is caused by a selective loss of hypocretin-producing neurons, but narcolepsy can also result from hypothalamic and rostral brainstem lesions.We describe a 38-year-old woman with severe daytime sleepiness, internuclear ophthalmoplegia, and bilateral delayed visual evoked potentials. Her multiple sleep latency test results demonstrated short sleep latencies and 4 sleep-onset rapid eye movement sleep periods, and her cerebrospinal fluid contained a low concentration of hypocretin. Magnetic resonance imaging showed T2 and fluid-attenuated inversion recovery hyperintensity along the walls of the third ventricle and aqueduct, which are consistent with acute disseminated encephalomyelitis.After treatment with steroids, this patient's subjective sleepiness, hypersomnia, and hypocretin deficiency partially improved.Autoimmune diseases such as acute disseminated encephalomyelitis can produce narcolepsy. Most likely, this narcolepsy is a consequence of demyelination and dysfunction of hypocretin pathways, but direct injury to the hypocretin neurons may also occur.
View details for Web of Science ID 000221362800021
View details for PubMedID 15148155
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Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis
NEUROLOGY
2004; 62 (1): 138-140
Abstract
Idiopathic narcolepsy is associated with deficient hypocretin transmission. Narcoleptic symptoms have recently been described in paraneoplastic encephalitis with anti-Ma2 antibodies. The authors measured CSF hypocretin-1 levels in six patients with anti-Ma2 encephalitis, and screened for anti-Ma antibodies in patients with idiopathic narcolepsy. Anti-Ma autoantibodies were not detected in patients with idiopathic narcolepsy. Four patients with anti-Ma2 encephalitis had excessive daytime sleepiness; hypocretin-1 was not detectable in their cerebrospinal fluid, suggesting an immune-mediated hypocretin dysfunction.
View details for Web of Science ID 000188010100037
View details for PubMedID 14718718
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Increased hypocretin-1 levels in cerebrospinal fluid after REM sleep deprivation
BRAIN RESEARCH
2004; 995 (1): 1-6
Abstract
Rat cisternal (CSF) hypocretin-1 in cerebrospinal fluid was measured after 6 or 96 h of REM sleep deprivation and following 24 h of REM sleep rebound. REM deprivation was found to increase CSF hypocretin-1 collected at zeitgeber time (ZT) 8 but not ZT0. Decreased CSF hypocretin levels were also observed at ZT8 after 24 h of REM sleep rebound. These results suggest that REM sleep deprivation activates and REM sleep rebound inhibits the hypocretin system. Increased hypocretin tone during REM deprivation may be important in mediating some of the effects of REM sleep deprivation such as antidepressant effects, hyperphagia and increased sympathetic activity.
View details for DOI 10.1016/j.brainres.2003.09.032
View details for Web of Science ID 000187747400001
View details for PubMedID 14644464
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CSF histamine and noradrenaline contents in narcolepsy and other sleep disorders
18th Annual Meeting of the Associated-Professional-Sleep-Societies
AMER ACAD SLEEP MEDICINE. 2004: 236–236
View details for Web of Science ID 000223169400532
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Diurnal variations of CSF hypocretin (HCRT) and changes in gene expression as detected by microarrays in young and old rats
18th Annual Meeting of the Associated-Professional-Sleep-Societies
AMER ACAD SLEEP MEDICINE. 2004: 382–382
View details for Web of Science ID 000223169400857
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Effects of IV and ICV hypocretin-1 (Orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin-ligand-deficient narcoleptic dog
SLEEP
2003; 26 (8): 953-959
Abstract
Using two different canine models of narcolepsy, we evaluated the therapeutic effects of hypocretin-1 on cataplexy and sleep.Intracerebroventricular administration of hypocretin-1 (10 and 30 nmol per dog) but not intravenous administration (up to 6 microg/kg) induced significant wakefulness in control dogs. However, hypocretin-1 had no effect on cataplexy or wakefulness in hypocretin receptor-2 gene (Hcrtr2) mutated narcoleptic Dobermans. Only very high intravenously doses of hypocretin-1 (96-384 microg/kg) penetrated the brain, to produce a short-lasting anticataplectic effect in a hypocretin-ligand-deficient animal.Hypocretin-1 administration, by central and systemic routes, does not improve narcoleptic symptoms in Hcrtr2 mutated Dobermans. Systemic hypocretin-1 hardly crosses the blood-brain barrier to produce therapeutic effects. The development of more centrally penetrable and longer lasting hypocretin analogs will be needed to further explore this therapeutic pathway in humans.
View details for Web of Science ID 000188205200008
View details for PubMedID 14746374
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Relationship between CSF hypocretin levels and hypocretin neuronal loss
EXPERIMENTAL NEUROLOGY
2003; 184 (2): 1010-1016
Abstract
The sleep disorder narcolepsy may now be considered a neurodegenerative disease, as there is a massive reduction in the number of neurons containing the neuropeptide, hypocretin (HCRT). Most narcoleptic patients have low to negligible levels of HCRT in the cerebrospinal fluid (CSF), and such measurements serve as an important diagnostic tool. However, the relationship between HCRT neurons and HCRT levels in CSF in human narcoleptics is not known and cannot be directly assessed. To identify this relationship in the present study, the neurotoxin, hypocretin-2-saporin (HCRT2-SAP), was administered to the lateral hypothalamus (LH) to lesion HCRT neurons. CSF was extracted at circadian times (ZT) 0 (time of lights-on) or ZT8 at various intervals (2, 4, 6, 12, 21, 36, 60 days) after neurotoxin administration. Compared to animals given saline in the LH, rats with an average loss of 73% of HCRT neurons had a 50% decline in CSF HCRT levels on day 60. The decline in HCRT levels was evident by day 6 and there was no recovery or further decrease. The decline in HCRT was correlated with increased REM sleep. Lesioned rats that were kept awake for 6 h were not able to release HCRT to match the output of saline rats. As most human narcoleptics have more than 80% reduction of CSF HCRT, the results from this study lead us to conclude that in these patients, virtually all of the HCRT neurons might be lost. In those narcoleptics where CSF levels are within the normal range, it is possible that not all of the HCRT neurons are lost and that the surviving HCRT neurons might be increasing output of CSF HCRT.
View details for DOI 10.1016/S0014-4886(03)00388-1
View details for Web of Science ID 000187634400049
View details for PubMedID 14769395
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CSF hypocretin levels in Guillain-Barre syndrome and other inflammatory neuropathies
NEUROLOGY
2003; 61 (6): 823-825
Abstract
CSF hypocretin-1 was measured in 28 Guillain-Barré syndrome (GBS), 12 Miller-Fisher syndrome, 12 chronic inflammatory demyelinating polyneuropathy (CIDP), and 48 control subjects. Seven GBS subjects had undetectably low hypocretin-1 levels (<100 pg/mL). Hypocretin-1 levels were moderately reduced in an additional 11 GBS, 5 Miller-Fisher syndrome, and 1 CIDP subject. Low levels in GBS occurred early in the disease and were associated with upper CNS level abnormalities.
View details for Web of Science ID 000185460600020
View details for PubMedID 14504329
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Differential kinetics of hypocretins in the cerebrospinal fluid after intracerebroventricular administration in rats
NEUROSCIENCE LETTERS
2003; 346 (3): 182-186
Abstract
Different potencies for hypocretin-1 and -2 in sleep-wake regulation and feeding after intracerebroventricular (ICV) administration have been reported. These differences were often explained by the selectivity of the two hypocretins for hypocretin receptor-1 and -2, but little attention has been paid to kinetics of hypocretin peptides. We investigated the kinetics of the ICV hypocretin-1 and -2 in rats. ICV hypocretin-1 (10 nmol) increased hypocretin-1 peptide level in the CSF by 800-fold from baseline with the elevation lasting over 4 h. In contrast, after ICV hypocretin-2 (10 nmol), no significant rise in the CSF was found. CSF hypocretin levels were significantly correlated with the biological activities of CSF hypocretin-1 and -2 using the Ca(2+) mobilization assay. Difference in the kinetics of hypocretins should be considered for interpreting ICV effects of hypocretins.
View details for DOI 10.1016/S0304-3940(03)00571-8
View details for Web of Science ID 000184192300015
View details for PubMedID 12853114
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The hypocretin/orexin system in health and disease
BIOLOGICAL PSYCHIATRY
2003; 54 (2): 87-95
Abstract
Using positional cloning in a canine model of narcolepsy and mouse gene knockouts, genes involved in the pathogenesis of narcolepsy in animals have been identified. Hypocretin/orexin ligand and hypocretin/orexin receptor genes are key to the pathogenesis of narcolepsy in animals. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in many cases. Hypocretins/orexins are novel hypothalamic neuropeptides involved in various hypothalamic mechanisms, such as energy homeostasis and neuroendocrine function. Hypocretin-deficient human narcolepsy appears to be a more complex condition than a simple sleep disorder, and it may serve as an important disease model for studying hypothalamic function in health and disease.
View details for DOI 10.1016/S0006-3223(03)00349-4
View details for Web of Science ID 000184213800001
View details for PubMedID 12873797
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Diurnal variation of cerebrospinal fluid hypocretin-1 (orexin-A) levels in control and depressed subjects
16th Annual Meeting of the Associated-Professional-Sleep-Societies
ELSEVIER SCIENCE INC. 2003: 96–104
Abstract
Hypocretins, excitatory neuropeptides at monoaminergic synapses, appear to regulate human sleep-wake cycles. Undetectable cerebrospinal fluid hypocretin-1 levels are seen in narcolepsy, which is frequently associated with secondary depression. Shortened rapid eye movement latency is observed in both narcolepsy and depression. Cerebrospinal fluid hypocretin-1 levels have not been reported in mood disorders.We examined hypocretin-1 levels in 14 control and 15 depressed subjects. Cerebrospinal fluid was drawn continuously in supine subjects for 24 hours with an indwelling intrathecal catheter under entrained light-dark conditions. Depressed subjects were studied before and after 5 weeks of sertraline (n=10, three nonresponders) or bupropion (n=5, two nonresponders).Hypocretin-1 levels varied slightly (amplitude 10%) but significantly across the diurnal cycle in control subjects, with amplitude significantly reduced in depression (3%). Levels were lowest at midday, surprising for a hypothetically wake-promoting peptide. Mean hypocretin levels trended higher in depressive than in control subjects. Hypocretin-1 levels decreased modestly but significantly after sertraline (-14%) but not bupropion.Our results are consistent with previous physiologic findings in depression indicating dampened diurnal variations in hypocretin-1. The finding that sertraline but not bupropion slightly decreased cerebrospinal fluid hypocretin-1 indicates a serotoninergic influence on hypocretin tone.
View details for DOI 10.1016/S0006-3223(03)01740-7
View details for Web of Science ID 000184213800002
View details for PubMedID 12873798
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Narcolepsy in a hypocretin/orexin-deficient chihuahua
VETERINARY RECORD
2003; 152 (25): 776-779
Abstract
A two-year-old male chihuahua suffered attacks of muscle weakness and immobility, although it had no family history of paroxysmal attacks. No neurological or blood biochemical abnormalities were recorded when it was first examined. The attacks were typically elicited by stimulation, such as feeding, and a case of sporadic narcolepsy-cataplexy was therefore suspected. Treatment orally three times a day with 1 mg/kg imipramine, was effective in reducing the attacks. The concentration of hypocretin-1/orexin A in the dog's cerebrospinal fluid was less than 80 pg/ml (22.5 pmol/litre), compared with normal canine levels of 250 to 350 pg/ml (70.0 to 98.3 pmol/litre), supporting a diagnosis of hypocretin-deficient narcolepsy.
View details for Web of Science ID 000183989400010
View details for PubMedID 12846289
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Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C
SLEEP
2003; 26 (4): 427-430
Abstract
Subjects with Niemann-Pick disease, type C have been reported to display narcolepsylike symptoms, including cataplexy. In this study, 5 patients with juvenile Niemann-Pick disease were evaluted for sleep abnormalities using nocturnal polysomnography, clinical evaluation, and the Multiple Sleep Latency Test. HLA typing and cerebrospinal fluid hypocretin levels were also evaluated in 4 patients. Niemann-Pick disease diagnosis was confirmed in all cases biochemically and by the presence of foam cells in the bone marrow.Deterioration of intellectual function; the presence of pyramidal, dystonic and cerebellar features; and splenomegaly were observed in all cases. Cataplexy was reported in 1 patient. Nocturnal polysomnography revealed disrupted sleep in all patients. Total sleep time, sleep efficiency, rapid eye movement sleep, and delta sleep amounts were decreased when compared to age-matched controls. Altered sleep patterns included sudden increases in muscle tone during delta sleep, electroencephalographic sigma activity connected with rapid eye movements and muscle atonia, atypical K-complexes and spindle activity, and the presence of alpha-delta sleep. All Niemann-Pick disease cases exhibited fragmentary myoclonus. Shortened mean sleep latencies were observed in 3 patients during the Multiple Sleep Latency Test, but sleep-onset rapid eye movement periods were observed only in the case with cataplexy. This patient was HLA DQB1*0602 positive, while the other subjects were HLA negative. Cerebrospinal fluid hypocretin-1 levels were reduced in 2 patients (1 with cataplexy) while in the 2 other patients, the levels were at the lower range of the normal values. Hypocretin levels in the Niemann-Pick disease group (204.8 +/- 39.3 pg/mL) were significantly reduced when compared to controls (265.8 +/- 48.8 pg/mL).The findings suggest that lysozomal storage abnormalities in Niemann-Pick disease patients may impact the hypothalamus and, more specifically, hypocretin-containing cells. These changes might be partially responsible for sleep abnormalities and cataplexy in patients with Niemann-Pick disease.
View details for Web of Science ID 000183452600006
View details for PubMedID 12841368
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Inhibition of rostral basal forebrain neurons promotes wakefulness and induces FOS in orexin neurons
EUROPEAN JOURNAL OF NEUROSCIENCE
2003; 17 (8): 1635-1645
Abstract
The present study examined whether the activities of the rostral basal forebrain neurons alter the activities of the orexin (also known as hypocretin) neurons in the tuberal part of the hypothalamus in rats. We performed microdialysis perfusion of the ventromedial portion of the rostral basal forebrain with the GABAA receptor agonist muscimol to inhibit focally the neuronal activities in the rostral basal forebrain. Then, we monitored sleep/wake behaviour and investigated the pattern of activities of orexin neurons by examining the expression of FOS as an indicator of cellular activation. Bilateral perfusion with muscimol (5, 15, and 50 micro m) produced a dose-dependent decrease in the amount of sleep. This perfusion with muscimol at 50 micro m produced FOS-like immunoreactivity in 37% of the orexin neurons located in the tuberal part of the hypothalamus, whereas the FOS-like immunoreactivity was sparse in orexin neurons of the sleeping control rats (P = 0.001 by Mann-Whitney U-test). Unilateral perfusion with muscimol (50 micro m) also suppressed sleep. In this case, FOS-like immunoreactivity was seen in 40% of the orexin neurons on the side ipsilateral to the perfusion site but only in 10% of orexin neurons on the contralateral side (P = 0.018 by Wilcoxon signed rank test). These functional data suggested that a sleep-generating element in the ventromedial part of the rostral basal forebrain provides an inhibitory influence on the activities of the orexin neurons in the tuberal part of the hypothalamus.
View details for DOI 10.1046/j.1460-9568.2003.02577.x
View details for Web of Science ID 000182539600012
View details for PubMedID 12752381
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The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A)
SLEEP MEDICINE
2003; 4 (1): 7-12
Abstract
Biological markers of narcolepsy with cataplexy (classical narcolepsy) include sleep-onset REM periods (SOREM) on multiple sleep latency tests (MSLT), HLA-DQB1*0602 positivity, low levels of cerebrospinal fluid (CSF) hypocretin-1 (orexin A), increased body mass index (BMI), and high levels of CSF leptin. The clinical borderland of narcolepsy and the diagnostic value of different markers of narcolepsy remain controversial and were assessed in a consecutive series of 27 patients with hypersomnia of (mainly) neurological origin.Diagnoses included classical narcolepsy (n=3), symptomatic narcolepsy (n=1), narcolepsy without cataplexy (n=4), idiopathic hypersomnia (n=5), hypersomnia associated with psychiatric disorders (n=5), and hypersomnia secondary to neurological disorders or of undetermined origin (n=9). Clinical assessment included BMI, Epworth Sleepiness Scale (ESS), Ullanlinna Narcolepsy Scale (UNS), and history of REM-symptoms (sleep paralysis, hallucinations). HLA-typing, electrophysiological studies (conventional polysomnography, MSLT, 1-week actigraphy), and measurements of CSF levels of hypocretin and leptin were also performed.Hypocretin-1 was undetectable in three patients with classic narcolepsy and detectable in the remaining 24 patients. Other narcoleptic markers also frequently found in patients without narcolepsy included ESS>14 (78% of 27 patients), UNS>14 (75%), REM symptoms (30%), sleep latencies on MSLT<5 min (41%), >/=2 SOREM (30%), DQB1*0602 positivity (52%), BMI>25 (52%), and increased CSF leptin (48%). Hypersomnia was documented by an increased time 'asleep' in 41% of patients. Overlapping clinical and electrophysiological findings were seen mostly in patients with narcolepsy without cataplexy, idiopathic hypersomnia, and psychiatric hypersomnia.(1) Hypocretin dysfunction is not the 'final common pathway' in the pathophysiology of most hypersomnolent syndromes that fall on the borderline for a diagnosis of narcolepsy. (2) The observed overlap among these hypersomnolent syndromes implies that current diagnostic categories are not entirely unambiguous. (3) A common hypothalamic, hypocretin-independent dysfunction may be present in some of these syndromes.
View details for DOI 10.1016/S1389-9457(02)00191-0
View details for Web of Science ID 000188838900004
View details for PubMedID 14592354
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Measurement of hypocretin/orexin content in the mouse brain using an enzyme immunoassay: the effect of circadian time, age and genetic background
PEPTIDES
2002; 23 (12): 2203-2211
Abstract
The hypocretins (1 and 2) have emerged as key regulators of sleep and wakefulness. We developed a high-throughput enzyme immunoassay (EIA) to measure total brain hypocretin levels from large numbers of mice. Hypocretin levels were not altered by circadian time or age. However, significant differences in one or both hypocretin peptides were observed between different mouse strains. We studied hypocretin levels in knockout and transgenic mouse models with obesity, circadian gene mutations or monoaminergic defects. Compared to controls, only histamine receptor knockouts had lower hypocretin levels. This was most pronounced in H1 receptor knockouts suggesting the existence of a positive feedback loop between hypocretin and histaminergic neurons.
View details for Web of Science ID 000180769800016
View details for PubMedID 12535700
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Transient total sleep loss in cerebral Whipple's disease: a longitudinal study
JOURNAL OF SLEEP RESEARCH
2002; 11 (4): 321-329
Abstract
A case with transient, almost complete sleep loss caused by cerebral manifestation of Whipple's disease (WD) is presented. Cerebral WD is rare and in most cases occurs after gastrointestinal infection. In our case, a progressive and finally almost complete sleep loss was the initial and predominant symptom. Polysomnographic studies in several consecutive nights and over 24 h showed a total abolition of the sleep-wake cycle with nocturnal sleep duration of less than 15 min. Endocrine tests revealed hypothalamic dysfunction with flattening of circadian rhythmicity of cortisol, TSH, growth hormone and melatonin. Cerebrospinal fluid (CSF) hypocretin was reduced. [18F]Deoxyglucose positron emission tomography (FDG-PET) revealed hypermetabolic areas in cortical and subcortical areas including the brainstem, which might explain sleep pathology and vertical gaze palsy. In the course of treatment with antibiotics and additional carbamazepine for 1 year, insomnia slowly and gradually improved. Endocrine investigations at 1-year follow-up showed persistent flattening of circadian rhythmicity. The FDG-PET indicated normalized metabolism in distinct regions of the brain stem which paralleled restoration of sleep length. The extent of sleep disruption in this case of organic insomnia was similar to cases of familial fatal insomnia, but was at least partially reversible with treatment.
View details for Web of Science ID 000179648600007
View details for PubMedID 12464100
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Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders
NATURE NEUROSCIENCE
2002; 5: 1071-1075
Abstract
Delineating the basic mechanisms that regulate sleep will likely result in the development of better treatments for sleep disorders. The hypothalamus is now recognized as a key center for sleep regulation, with hypothalamic neurotransmitter systems providing the framework for therapeutic advances. An increased awareness of the close interaction between sleep and homeostatic systems is also emerging. Progress has occurred in the understanding of narcolepsy--molecular techniques have identified the lateral hypothalamic hypocretin (orexin) neuropeptide system as key to the disorder. Other sleep disorders are now being tackled in the same way and are likely to yield to efforts combining basic and clinical research. Here we highlight the role of the hypothalamus in sleep physiology and discuss neurotransmitter systems, such as adenosine, dopamine, GABA, histamine and hypocretin, that may have therapeutic applications for sleep disorders.
View details for DOI 10.1038/nn944
View details for Web of Science ID 000179041300017
View details for PubMedID 12403989
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The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias
ARCHIVES OF NEUROLOGY
2002; 59 (10): 1553-1562
Abstract
Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels.To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy.Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-1 were studied in a case series of patients with sleep disorders from 1999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-1 levels best predictive for International Classification of Sleep Disorders (ICSD)-defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-1 levels.Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif.There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB1*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders).Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies.Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity, and clinical and polysomnographic features.HLA-DQB1*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs 17% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-1 levels below 110 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB1*0602-positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB1*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and 1 with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n = 194). Intermediate (n = 30) and low (n = 3) levels were observed in various acute neuropathologic conditions.Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).
View details for Web of Science ID 000178560100005
View details for PubMedID 12374492
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Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome
NEUROLOGY
2002; 59 (4): 639-641
Abstract
Hypocretin-1 levels were increased in evening CSF samples from subjects with restless legs syndrome, indicating altered hypocretin transmission in this sleep disorder. Increases in CSF hypocretin-1 levels were most striking in patients with early-onset restless legs syndrome.
View details for Web of Science ID 000177613500035
View details for PubMedID 12196669
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Article reviewed: Plasma orexin-A is lower in patients with narcolepsy.
Sleep medicine
2002; 3 (4): 377-378
View details for PubMedID 14592205
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HLA and hypocretin studies in Korean patients with narcolepsy
SLEEP
2002; 25 (4): 440-444
Abstract
Very few studies have evaluated narcolepsy in Asian countries, outside of Japan. Our goal was to study narcolepsy at the genetic, clinical and pathophysiological level in Korea.Prospective study of consecutive patients and age matched controls. Clinical data ascertained from the Stanford Sleep Inventory, Polysomnography and MSLT data, as well as clinical notes. High resolution DRB1 and DQB1 typing in all subjects and studies of CSF hypocretin-1 was also evaluated in a subset of patients.20 patients diagnosed at St. Vincent and Korea University Hospitals (Seoul, Korea). 21 Korean control subjects.N/A.For narcoleptic subjects, mean age was 28.2 years old and 45% were female. Mean BMI was 23.9+/-3.4 kg/m2, a significantly higher value than that expected in an age- and sex-matched sample (p<0.01). All patients had sleepiness and cataplexy while the prevalence of other symptoms ranged from 60-75%. All but 2 subjects were HLA-DR15 (DR2), DQB1*0602 positive (90%). This high DQB1*0602 percentage compared with 24% DQB1*0602 positivity in 21 control Koreans. Protective effects were observed for the DQB1*0601 and DRB1*0406 alleles, Hypocretin (orexin) CSF studies were also performed in 6 cataplectic subjects, all of which had undetectable CSF hypocretin levels. Two of these subjects had started narcolepsy less than 1 year before analysis yet had undetectable hypocretin levels.These results illustrate the similarity of narcolepsy-cataplexy in Korea in comparisons with other more studied populations. We also identified a new potential HLA protective subtype, HLA-DRB1*0406.
View details for Web of Science ID 000176089100011
View details for PubMedID 12071546
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Hypocretin stimulates [(35)]GTP gamma S binding in Hcrtr 2-transfected cell lines and in brain homogenate
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
2002; 294 (3): 615-620
Abstract
In vitro functional analyses of hypocretin/orexin receptor systems were performed using [(125)I]hypocretin radioreceptor and hypocretin-stimulated [(35)S]GTP gamma S binding assay in cell lines expressing human or canine (wild-type and narcoleptic-mutation) hypocretin receptor 2 (Hcrtr 2). Hypocretin-2 stimulated [(35)S]GTP gamma S binding in human and canine Hcrtr 2 expressing cell lines, while cell lines expressing the mutated canine Hcrtr 2 did not exhibit specific binding for [(125)I]hypocretin or hypocretin-stimulated [(35)S]GTP gamma S. In rat brain homogenates, regional specific hypocretin-stimulated [(35)S]GTP gamma S binding was also observed. Hypocretin-stimulated [(35)S]GTP gamma S binding, may thus be a useful functional assay for hypocretin receptors in both cell lines and brain tissue homogenates.
View details for Web of Science ID 000176364700017
View details for PubMedID 12056812
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Analysis of onset location, laterality and propagation of cataplexy in canine narcolepsy
26th Annual Meeting of the Japanese-Society-of-Sleep-Research
WILEY-BLACKWELL. 2002: 275–76
Abstract
Hypocretin deficiency is involved in most cases of human narcolepsy. Although cataplexy is pathognomonic of narcolepsy, mechanisms of induction of cataplexy are largely unknown. Patterns of occurrence of cataplectic attacks (i.e. onset location, laterality, and propagation of attacks) in hypocretin receptor 2-mutated narcoleptic Dobermans were characterized in order to understand the basic mechanism of this abnormal sleep-related atonia. Most cataplexy attacks were bilateral (98%) and were initiated in the hind legs (80%). Progression of attacks was also seen (49%) and atonia during propagation was most often bilateral (94%). Involvement of abnormal inactivation of bilateral pathways to the spinal motoneurones due to a deficiency in hypocretin neurotransmission is suggested in the occurrence of cataplexy.
View details for Web of Science ID 000176033900033
View details for PubMedID 12047593
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Hypocretin-1 (orexin-A) concentrations in cerebrospinal fluid are low in patients with Guillain-Barre syndrome
26th Annual Meeting of the Japanese-Society-of-Sleep-Research
WILEY-BLACKWELL. 2002: 273–74
Abstract
It is reported that cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) concentrations in patients with narcolepsy are significantly low. Human narcolepsy is also known to be closely associated with a specific human histocompatibility leukocyte antigen (HLA), suggesting that autoimmunity is involved in the pathophysiology of the disease. Thus, it is important to know whether hypocretin changes are found in definite neuroimmunological diseases such as multiple sclerosis and Guillain-Barré syndrome (GBS). The results of the present study indicate that some patients with GBS have lower levels of CSF hypocretin-1.
View details for Web of Science ID 000176033900032
View details for PubMedID 12047592
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CSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture
PSYCHIATRY RESEARCH
2002; 110 (1): 1-7
Abstract
Hypocretins/orexins are newly identified peptides of hypothalamic origin. Hypocretin deficiency is involved in the sleep disorder narcolepsy, suggesting the importance of hypocretin neurotransmission for the regulation of sleep. Hypocretin is known to excite midbrain dopaminergic neurons and to induce hyperactivity and stereotypy in animals. Altered hypocretin neurotransmission might therefore be involved in schizophrenia, since an involvement of dopaminergic mechanisms and an association with sleep disturbance are well demonstrated in patients with schizophrenia. Hypocretin is also known to affect the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH). In the current study, we measured CSF hypocretin levels in 12 controls and 13 patients with chronic schizophrenia associated with moderate sleep disturbance, such as longer sleep onset latency, decreased total sleep time and decreased sleep efficacy. No difference in CSF hypocretin levels between schizophrenia and control subjects was found. CSF hypocretin levels were positively correlated with CSF CRH levels in the patient, control and combined subject populations, but the correlation did not reach statistical significance in any population. The hypocretin levels in schizophrenic patients were, however, positively and significantly correlated with sleep latency, one of the most consistent sleep abnormalities seen in schizophrenia. This correlation was not significant in controls, and no other significant correlation between CSF hypocretin levels and any measure of sleep architecture in either patients or controls was observed. Further studies of whether CNS hypocretin neurotransmission is involved in sleep and neuroendocrine abnormalities seen in patients with schizophrenia and other psychiatric conditions are warranted.
View details for Web of Science ID 000176095700001
View details for PubMedID 12007588
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Hypocretin-1 (Orexin-A) levels in human lumbar CSF in different age groups: Infants to elderly persons
SLEEP
2002; 25 (3): 337-339
Abstract
Recent CSF and postmortem brain hypocretin measurements in human narcolepsy suggest that hypocretin deficiency is involved in the pathophysiology of the disease. In this study, we measured CSF hypocretin-1 levels in various age ranges from infants to elder people to investigate the age-dependent change of hypocretin concentrations.CSF hypocretin levels were compared by age groups and gender. ANOVA was used to examine the influences of these two parameters on CSF hypocretin levels.University-based sleep and biology laboratory.Two hundred seventy two patients were included in this study, with 157 males and 115 females (0-79 years old).CSF samples were obtained by lumber punctures with informed consents.Hypocretin-1 levels are not different in respect to gender or age, although our samples constitute a heterogeneous group with various disease conditions. CSF hypocretin-1 levels in infants under 4 months are similar to those in adults.Early maturation of hypocretin transmission is suggested. No age- or gender-dependent changes in CSF hypocretin is observed.
View details for Web of Science ID 000175048800010
View details for PubMedID 12003164
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Diurnal variation of CSF hypocretin-1 (orexin A) levels in control and depressed subjects
AMER ACAD SLEEP MEDICINE. 2002: A12–A13
View details for Web of Science ID 000174927200019
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CSF hypocretin-1 (orexin-A) levels in narcolepsy without cataplexy and idiopathic hypersomnia.
AMER ACAD SLEEP MEDICINE. 2002: A356–A356
View details for Web of Science ID 000174927200498
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CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia
JOURNAL OF SLEEP RESEARCH
2002; 11 (1): 91-93
Abstract
We measured cerebrospinal fluid (CSF) hypocretin-1 levels in 11 patients with narcolepsy-cataplexy, five with narcolepsy without cataplexy and 12 with idiopathic hypersomnia (IHS). All patients were Japanese. As reported in Caucasian patients, undetectable or very low hypocretin-1 levels were observed in most (9 out of 11) Japanese narcolepsy--cataplexy patients. Our hypocretin-deficient narcoleptics included three prepubertal cases within few months after the disease onset. All nine hypocretin-deficient patients were human leuckocyte antigen (HLA) DR2 positive, while two who had normal CSF hypocretin-1 levels were HLA DR2 negative. In contrast, none of the narcolepsy without cataplexy and IHS subjects had undetectable low levels. Low CSF hypocretin-1 is therefore very specific for HLA DR2 positive narcolepsy-cataplexy, and the deficiency is likely to be established at the early stage of the disease.
View details for Web of Science ID 000174241100012
View details for PubMedID 11869432
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CSF hypocretin/orexin levels in narcolepsy and other neurological conditions
NEUROLOGY
2001; 57 (12): 2253-2258
Abstract
To examine the specificity of low CSF hypocretin-1 levels in narcolepsy and explore the potential role of hypocretins in other neurologic disorders.A method to measure hypocretin-1 in 100 microL of crude CSF sample was established and validated. CSF hypocretin-1 was measured in 42 narcolepsy patients (ages 16-70 years), 48 healthy controls (ages 22-77 years,) and 235 patients with various other neurologic conditions (ages 0-85 years).As previously reported, CSF hypocretin-1 levels were undetectably low (<100 pg/mL) in 37 of 42 narcolepsy subjects. Hypocretin-1 levels were detectable in all controls (224-653 pg/mL) and all neurologic patients (117-720 pg/mL), with the exception of three patients with Guillain-Barré syndrome (GBS). Hypocretin-1 was within the control range in most neurologic patients tested, including patients with AD, PD, and MS. Low but detectable levels (100-194 pg/mL) were found in a subset of patients with acute lymphocytic leukemia, intracranial tumors, craniocerebral trauma, CNS infections, and GBS.Undetectable CSF hypocretin-1 levels are highly specific to narcolepsy and rare cases of GBS. Measuring hypocretin-1 levels in the CSF of patients suspected of narcolepsy is a useful diagnostic procedure. Low hypocretin levels are also observed in a large range of neurologic conditions, most strikingly in subjects with head trauma. These alterations may reflect focal lesions in the hypothalamus, destruction of the blood brain barrier, or transient or chronic hypofunction of the hypothalamus. Future research in this area is needed to establish functional significance.
View details for Web of Science ID 000172891500018
View details for PubMedID 11756606
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Decreased brain histamine content in hypocretin/orexin receptor-2 mutated narcoleptics dogs
NEUROSCIENCE LETTERS
2001; 313 (3): 125-128
Abstract
A growing amount of evidence suggests that a deficiency in hypocretin/orexin neurotransmission is critically involved in animal and human forms of narcolepsy. Since hypocretin-containing neurons innervate and excite histaminergic tuberomammillary neurons, altered histaminergic neurotransmission may also be involved in narcolepsy. We found a significant decrease in histamine content in the cortex and thalamus, two structures important for histamine-mediated cortical arousal, in Hcrtr-2 mutated narcoleptic Dobermans. In contrast, dopamine and norepinephrine contents in these structures were elevated in narcoleptic animals, a finding consistent with our hypothesis of altered catecholaminergic transmission in these animals. Considering the fact that histamine promotes wakefulness, decreases in histaminergic neurotransmission may also account for the sleep abnormalities in hypocretin-deficient narcolepsy.
View details for Web of Science ID 000172056000004
View details for PubMedID 11682143
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Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities
EUROPEAN JOURNAL OF NEUROSCIENCE
2001; 14 (7): 1075-1081
Abstract
Hypocretins/orexins are neuropeptides implicated in sleep regulation and the sleep disorder narcolepsy. In order to examine how hypocretin activity fluctuates across 24 h with respect to the sleep-wake cycle, we measured changes in extracellular hypocretin-1 levels in the lateral hypothalamus and medial thalamus of freely moving rats with simultaneous sleep recordings. Hypocretin levels exhibited a robust diurnal fluctuation; levels slowly increased during the dark period (active phase), and decreased during the light period (rest phase). Levels were not correlated with the amount of wake or sleep in each period. Although an acute 4-h light-shift did not alter hypocretin levels, 6-h sleep deprivation significantly increased hypocretin release during the forced-wake period. Hypocretin activity is, thus, likely to build up during wakefulness and decline with the occurrence of sleep. These findings, together with the fact that a difficulty in maintaining wakefulness during the daytime is one of the primary symptoms of hypocretin-deficient narcolepsy, suggest that hypocretin activity may be critical in opposing sleep propensity during periods of prolonged wakefulness.
View details for Web of Science ID 000171795700004
View details for PubMedID 11683899
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Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy
ANNALS OF NEUROLOGY
2001; 50 (3): 381-388
Abstract
Hypocretins (orexins) are hypothalamic neuropeptides involved in sleep and energy homeostasis. Hypocretin mutations produce narcolepsy in animal models. In humans, narcolepsy is rarely due to hypocretin mutations, but this system is deficient in the cerebrospinal fluid (CSF) and brain of a small number of patients. A recent study also indicates increased body mass index (BMI) in narcolepsy. The sensitivity of low CSF hypocretin was examined in 38 successive narcolepsy-cataplexy cases [36 human leukocyte antigen (HLA)-DQB1*0602-positive] and 34 matched controls (15 controls and 19 neurological patients). BMI and CSF leptin levels were also measured. Hypocretin-1 was measurable (169 to 376 pg/ml) in all controls. Levels were unaffected by freezing/thawing or prolonged storage and did not display any concentration gradient. Hypocretin-1 was dramatically decreased (<100 pg/ml) in 32 of 38 patients (all HLA-positive). Four patients had normal levels (2 HLA-negative). Two HLA-positive patients had high levels (609 and 637 pg/ml). CSF leptin and adjusted BMI were significantly higher in patients versus controls. We conclude that the hypocretin ligand is deficient in most cases of human narcolepsy, providing possible diagnostic applications. Increased BMI and leptin indicate altered energy homeostasis. Sleep and energy metabolism are likely to be functionally connected through the hypocretin system.
View details for Web of Science ID 000170803200014
View details for PubMedID 11558795
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Low cerebrospinal fluid hypocretin levels found in familial narcolepsy
SLEEP MEDICINE
2001; 2 (5): 451-453
Abstract
This report describes abnormal hypocretin neurotransmission in a case of familial narcolepsy.Narcolepsy is a chronic, often-disabling central nervous system disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep features including cataplexy, a loss of muscle tone triggered by emotion. The cause of human narcolepsy is unknown. Several familial cases have been described, but most cases are sporadic (95%). An abnormality of hypocretin neurotransmission has been found in a majority of sporadic cases.Hypocretin-1 levels were measured in the cerebrospinal fluid of the narcoleptic proband of a family with several affected members.The proband was found to have a hypocretin-1 deficiency.Abnormal hypocretin neurotransmission is found in familial, as well as sporadic, narcolepsy.
View details for Web of Science ID 000208301200011
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Low cerebrospinal fluid hypocretin levels found in familial narcolepsy.
Sleep medicine
2001; 2 (5): 451-453
Abstract
This report describes abnormal hypocretin neurotransmission in a case of familial narcolepsy.Narcolepsy is a chronic, often-disabling central nervous system disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep features including cataplexy, a loss of muscle tone triggered by emotion. The cause of human narcolepsy is unknown. Several familial cases have been described, but most cases are sporadic (95%). An abnormality of hypocretin neurotransmission has been found in a majority of sporadic cases.Hypocretin-1 levels were measured in the cerebrospinal fluid of the narcoleptic proband of a family with several affected members.The proband was found to have a hypocretin-1 deficiency.Abnormal hypocretin neurotransmission is found in familial, as well as sporadic, narcolepsy.
View details for PubMedID 14592396
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A hypersomnolent girl with decreased CSF hypocretin level after removal of a hypothalamic tumor
NEUROLOGY
2001; 56 (12): 1775-1776
View details for Web of Science ID 000169424200034
View details for PubMedID 11425955
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Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke
NEUROLOGY
2001; 56 (12): 1751-1753
Abstract
Idiopathic narcolepsy usually results from a loss of the hypothalamic neuropeptide orexin (hypocretin), but the cause of secondary narcolepsy resulting from focal brain lesions is unknown. The authors describe a young man who developed narcolepsy after a large hypothalamic stroke. His lesion included much of the hypothalamic region in which orexin is produced, and his CSF concentration of orexin was low. The authors hypothesize that a loss of orexin neurons or their relevant targets may be the specific neuropathology causing this and many other cases of secondary narcolepsy.
View details for Web of Science ID 000169424200026
View details for PubMedID 11425947
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Narcoleptic canines display periodic leg movements during sleep
25th Annual Meeting of the Japanese-Society-of-Sleep-Research (JSSR)
WILEY-BLACKWELL. 2001: 243–44
Abstract
Periodic leg movements during sleep (PLMS) is a high prevalent sleep disorder of unknown etiology. The disease is pharmacologically treated with dopaminergic agonists (i.e. D2/D3 agonists) and opiates. Periodic leg movements during sleep often occur in narcoleptic patients. We observed that narcoleptic canines, like narcoleptic humans, also exhibit jerky, unilateral or bilateral slow leg movements during sleep. The movements in dogs are characterized by repetitive dorsiflexions of the ankle, lasting 0.5-1.5 s, and occur at regular intervals of 3-20 s, thus showing similarities to PLMS in humans. The observation that D2/D3 agonists aggravate cataplexy in narcoleptic dogs suggests that altered dopaminergic regulation in canine narcolepsy may play a critical role in both cataplexy and PLMS. Our canines may therefore be an invaluable resource in PLMS research.
View details for Web of Science ID 000169754800033
View details for PubMedID 11422858
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Hypocretin levels in sporadic and familial cases of canine narcolepsy
NEUROBIOLOGY OF DISEASE
2001; 8 (3): 525-534
Abstract
Familial and sporadic forms of narcolepsy exist in both humans and canines. Mutations in the hypocretin receptor 2 gene (Hcrtr 2) cause canine familial narcolepsy. In humans, mutations in hypocretin-related genes are rare, but cerebrospinal fluid (CSF) hypocretin-1 is undetectable in most sporadic cases. Using the canine model, we investigated ( 1 ) whether hypocretin deficiency is involved in sporadic cases and ( 2 ) whether alterations in hypocretin neurons or ligand levels also contribute to the phenotype in Hcrtr 2 mutants. We found that hypocretins were undetectable in the brains of three of three and the CSF of two of two sporadic narcoleptic dogs tested. In contrast, hypocretin levels were not altered in brains and CSF of genetically narcoleptic Dobermans, and hypocretin-containing neurons were of normal appearance. Therefore, multiple hypocretin-related etiologies are likely to be involved in canine narcolepsy. The presence of hypocretin peptides in Hcrtr 2-mutated animals suggests that neurotransmission through Hcrtr 1 may be intact, arguing for a preferential importance of Hcrtr 2-mediated function in narcolepsy.
View details for Web of Science ID 000169459000014
View details for PubMedID 11442359
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Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation
NEUROREPORT
2001; 12 (5): 993-997
Abstract
Hypocretin-1 is consistently detectable in the CSF of healthy human subjects, but is absent in narcoleptics. However, functional roles of CSF hypocretin are largely unknown. We examined fluctuation of CSF hypocretin-1 across 24 h and in response to food restriction in rats. Hypocretin-1 levels were high during the dark period when animals were active, but decreased by 40% toward the end of the light (rest) period. After 72 h food deprivation hypocretin-1 levels during the rest phase increased to concentrations similar to those seen during the baseline active phase; however, no increase in response to food deprivation was observed during the active phase. These results indicate an important link between circadian control of sleep and energy homeostasis via the hypocretin system.
View details for Web of Science ID 000167905600027
View details for PubMedID 11303775
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Diagnostic value of low CSF hypocretin/orexin levels in human narcolepsy
AMER ACAD SLEEP MEDICINE. 2001: A95–A96
View details for Web of Science ID 000168230900157
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Dopaminergic role in stimulant-induced wakefulness
JOURNAL OF NEUROSCIENCE
2001; 21 (5): 1787-1794
Abstract
The role of dopamine in sleep regulation and in mediating the effects of wake-promoting therapeutics is controversial. In this study, polygraphic recordings and caudate microdialysate dopamine measurements in narcoleptic dogs revealed that the wake-promoting antinarcoleptic compounds modafinil and amphetamine increase extracellular dopamine in a hypocretin receptor 2-independent manner. In mice, deletion of the dopamine transporter (DAT) gene reduced non-rapid eye movement sleep time and increased wakefulness consolidation independently from locomotor effects. DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine. Thus, dopamine transporters play an important role in sleep regulation and are necessary for the specific wake-promoting action of amphetamines and modafinil.
View details for Web of Science ID 000167129700040
View details for PubMedID 11222668
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The role of histamine in a hypocretin (orexin)-deficient sleep disorder, narcolepsy
5th International Histamine Symposium
ELSEVIER SCIENCE BV. 2001: 247–251
View details for Web of Science ID 000174224300035
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Hypocretin deficiency in familial symptomatic narcolepsy
ANNALS OF NEUROLOGY
2001; 49 (1): 136-137
View details for Web of Science ID 000166968000023
View details for PubMedID 11198287
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Is narcolepsy a REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans
NEUROSCIENCE RESEARCH
2000; 38 (4): 437-446
Abstract
Narcolepsy is a chronic sleep disorder marked by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Since the discovery of sleep onset REM periods (SOREMPs) in narcoleptic patients, narcolepsy has often been regarded as a disorder of REM sleep generation: REM sleep intrudes in active wake or at sleep onset, resulting in cataplexy, sleep paralysis, or hypnagogic hallucinations. However, this hypothesis has not been experimentally verified. In the current study, we characterized the sleep abnormalities of genetically narcoleptic-cataplectic Dobermans, a naturally occurring animal model of narcolepsy, in order to verify this concept. Multiple sleep latency tests during the daytime revealed that narcoleptic Dobermans exhibit a shorter sleep latency and a higher frequency of SOREMPs, compared to control Dobermans. The total amount of time spent in wake and sleep during the daytime is not altered in narcoleptic dogs, but their wake and sleep patterns are fragmented, and state transitions into and from wake and other sleep stages are altered. A clear 30 min REM sleep cyclicity exists in both narcoleptic and control dogs, suggesting that generation of the ultradian rhythm of REM sleep is not altered in narcoleptics. In contrast, cataplexy displays no cyclicity and can be elicited in narcoleptic animals anytime with emotional stimulation and displays no cyclicity. Stimulation of a cholinoceptive site in the basal forebrain induces a long-lasting attack of cataplexy in narcoleptic dogs; however, bursts of rapid eye movements during this state still occur with a 30 min cyclicity. Sites and mechanisms for triggering cataplexy may therefore be different from those for REM sleep. Cataplexy and a dysfunction in the maintenance of vigilance states, but not abnormal REM sleep generation, may therefore be central to narcolepsy.
View details for Web of Science ID 000166120200013
View details for PubMedID 11164570
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Sulpiride, a D2/D3 blocker, reduces cataplexy but not REM sleep in canine narcolepsy
NEUROPSYCHOPHARMACOLOGY
2000; 23 (5): 528-538
Abstract
Cataplexy, an abnormal manifestation of REM sleep atonia, is currently treated with antidepressants. These medications also reduce physiological REM sleep and induce nocturnal sleep disturbances. Because a recent work on canine narcolepsy suggests that the mechanisms for triggering cataplexy are different from those for REM sleep, we hypothesized that compounds which act specifically on cataplexy, but not on REM sleep, could be developed. Canine studies also suggest that the dopamine D2/D3 receptor mechanism is specifically involved in the regulation of cataplexy, but little evidence suggests that this mechanism is important for REM sleep regulation. We therefore assessed the effects of sulpiride, a commonly used D2/D3 antagonist, on cataplexy and sleep in narcoleptic canines to explore the possible clinical application of D2/D3 antagonists for the treatment of human narcolepsy. Both acute and chronic oral administration of sulpiride (300 mg/dog, 600 mg/dog) significantly reduced cataplexy without noticeable side effects. Interestingly, the anticataplectic dose of sulpiride did not significantly reduce the amount of REM sleep. Sulpiride (and other D2/D3 antagonists) may therefore be an attractive new therapeutic indication in human narcolepsy.
View details for Web of Science ID 000089867500005
View details for PubMedID 11027918
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A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains
NATURE MEDICINE
2000; 6 (9): 991-997
Abstract
We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.
View details for Web of Science ID 000089190500030
View details for PubMedID 10973318
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Chronic oral administration of CG-3703, a thyrotropin releasing hormone analog, increases wake and decreases cataplexy in canine narcolepsy
NEUROPSYCHOPHARMACOLOGY
2000; 23 (1): 34-45
Abstract
The effects on cataplexy and daytime sleep of acute and chronic oral administration of CG-3703, a potent TRH analog were assessed in canine narcolepsy. CG-3703 was found to be orally active and to reduce cataplexy (0.25 to 16 mg/kg) and sleep (8 and 16 mg/kg) in a dose-dependent manner. Two-week oral administration of CG-3703 (16 mg/kg) significantly reduced cataplexy and daytime sleep. The anticataplectic effects of CG-3703 were not associated with changes in general behavior, heart rate, blood pressure, rectal temperature, blood chemistry and thyroid function. Although drug tolerance for the effects on cataplexy and sleep were observed during the second week of chronic drug administration, therapeutic efficacy on cataplexy was improved with individual dose adjustment (final dose range: 16 to 28 mg/kg, p.o.). These results suggest that TRH analogs could be a promising new form of treatment for human narcolepsy.
View details for Web of Science ID 000087772700004
View details for PubMedID 10869884
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Narcolepsy: genetic predisposition and neuropharmacological mechanisms. REVIEW ARTICLE.
Sleep medicine reviews
2000; 4 (1): 57-99
Abstract
Narcolepsy is a disabling sleep disorder characterized by excessive daytime somnolence (EDS), cataplexy and REM sleep-related abnormalities. It is a frequently-occurring but under-diagnosed condition that affects 0.02 to 0.18% of the general population in various countries. Although most cases occur sporadically, familial clustering may be observed; the risk of a first-degree relative of a narcoleptic developing narcolepsy is 10-40 times higher than in the general population. The disorder is tightly associated with the specific human leukocyte antigen (HLA) allele, DQB1*0602 [most often in combination with HLA-DR2 (DRB1*15)]. Genetic transmission is, however, likely to be polygenic in most cases, and genetic factors other than HLA-DQ are also likely to be implicated. In addition, environmental factors are involved in disease predisposition; most monozygotic twins pairs reported in the literature are discordant for narcolepsy. Narcolepsy was reported to exist in canines in the early 1970s. Both sporadic and familial cases are also observed in this animal species. A highly-penetrant single autosomal recessive gene, canarc-1, is involved in the transmission of narcolepsy in Doberman pinschers and Labrador retrievers. Positional cloning of this gene is in progress, and a human homologue of this gene, or a gene with a functional relationship to canarc-1, might be involved in some human cases. Human narcolepsy is currently treated with central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep. These treatments are purely symptomatic and induce numerous side effects. These compounds disturb nocturnal sleep in many patients, and tolerance may develop as a result of continuous treatment. The canine model is an invaluable resource for studying the pharmacological and physiological control of EDS and cataplexy. Experiments using canine narcolepsy have demonstrated that increased cholinergic and decreased monoaminergic transmission are likely to be at the basis of the pathophysiology of the disorder. Pharmacological studies have shown that blockade of norepinephrine uptake mediates the anticataplectic effect of currently prescribed antidepressants, while blockade of dopamine uptake and/or stimulation of dopamine release mediates the awake-promoting effect of CNS stimulants. Studies in canine narcolepsy also suggest that mechanisms and brain sites for triggering cataplexy are not identical to those regulating REM sleep. It may thus be possible to develop new pharmacological compounds that specifically target abnormal symptoms in narcolepsy, but do not disturb physiological sleep/wake cycles. (See also postscript remarks).
View details for PubMedID 12531161
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Inheritance of von Willebrand's disease in a colony of Doberman Pinschers
AMERICAN JOURNAL OF VETERINARY RESEARCH
2000; 61 (2): 115-120
Abstract
To determine the mode of inheritance of von Willebrand's disease (vWD) and perform linkage analysis between vWD and coat color or narcolepsy in a colony of Doberman Pinschers.159 Doberman Pinschers.von Willebrand factor antigen (vWF:Ag) concentration was measured by use of ELISA, and results were used to classify dogs as having low (< 20%), intermediate (20 to 65%), or high (> 65%) vWF:Ag concentration, compared with results of analysis of standard pooled plasma. Buccal bleeding time was measured, and mode of inheritance of vWD was assessed by pedigree analysis.von Willebrand's disease was transmitted as a single autosomal gene defect. Results suggested that 27.04% of dogs were homozygous for vWD, 62.26% were heterozygous, and 10.69% did not have the defect. Most homozygous and some heterozygous dogs had prolonged bleeding times. Dogs with diluted coat colors (blue and fawn) were significantly overrepresented in the homozygous group, compared with black and red dogs, but a significant link between vWD and coat color was not detected.von Willebrand's disease is transmitted as an autosomal dominant trait with variable penetrance; most dogs in this colony (89.3%) were carriers of vWD. Homozygosity for vWD is not likely to be lethal. Some heterozygous dogs have prolonged bleeding times. An association between diluted coat colors and vWD may exist.
View details for Web of Science ID 000085055600002
View details for PubMedID 10685679
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Narcolepsy: genetic predisposition and neuropharmacological mechanisms
SLEEP MEDICINE REVIEWS
2000; 4 (1): 57-99
Abstract
Narcolepsy is a disabling sleep disorder characterized by excessive daytime somnolence (EDS), cataplexy and REM sleep-related abnormalities. It is a frequently-occurring but under-diagnosed condition that affects 0.02 to 0.18% of the general population in various countries. Although most cases occur sporadically, familial clustering may be observed; the risk of a first-degree relative of a narcoleptic developing narcolepsy is 10-40 times higher than in the general population. The disorder is tightly associated with the specific human leukocyte antigen (HLA) allele, DQB1*0602 [most often in combination with HLA-DR2 (DRB1*15)]. Genetic transmission is, however, likely to be polygenic in most cases, and genetic factors other than HLA-DQ are also likely to be implicated. In addition, environmental factors are involved in disease predisposition; most monozygotic twins pairs reported in the literature are discordant for narcolepsy. Narcolepsy was reported to exist in canines in the early 1970s. Both sporadic and familial cases are also observed in this animal species. A highly-penetrant single autosomal recessive gene, canarc-1, is involved in the transmission of narcolepsy in Doberman pinschers and Labrador retrievers. Positional cloning of this gene is in progress, and a human homologue of this gene, or a gene with a functional relationship to canarc-1, might be involved in some human cases. Human narcolepsy is currently treated with central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep. These treatments are purely symptomatic and induce numerous side effects. These compounds disturb nocturnal sleep in many patients, and tolerance may develop as a result of continuous treatment. The canine model is an invaluable resource for studying the pharmacological and physiological control of EDS and cataplexy. Experiments using canine narcolepsy have demonstrated that increased cholinergic and decreased monoaminergic transmission are likely to be at the basis of the pathophysiology of the disorder. Pharmacological studies have shown that blockade of norepinephrine uptake mediates the anticataplectic effect of currently prescribed antidepressants, while blockade of dopamine uptake and/or stimulation of dopamine release mediates the awake-promoting effect of CNS stimulants. Studies in canine narcolepsy also suggest that mechanisms and brain sites for triggering cataplexy are not identical to those regulating REM sleep. It may thus be possible to develop new pharmacological compounds that specifically target abnormal symptoms in narcolepsy, but do not disturb physiological sleep/wake cycles. (See also postscript remarks).
View details for Web of Science ID 000086058200006
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Hypocretin (orexin) deficiency in human narcolepsy
LANCET
2000; 355 (9197): 39-40
Abstract
Alterations in the hypocretin receptor 2 and preprohypocretin genes produce narcolepsy in animal models. Hypocretin was undetectable in seven out of nine people with narcolepsy, indicating abnormal hypocretin transmission.
View details for Web of Science ID 000085049200016
View details for PubMedID 10615891
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Implication of dopaminergic mechanisms in the wake-promoting effects of amphetamine: A study of D- and L-derivatives in canine narcolepsy
NEUROSCIENCE
2000; 99 (4): 651-659
Abstract
Using a canine model of narcolepsy and selective DA and NE uptake inhibitors, we have recently shown that DA uptake inhibition promotes wakefulness, while NE uptake inhibition inhibits rapid eye movement sleep and cataplexy. In order to further delineate the respective roles of the dopaminergic and noradrenergic systems in the pharmacological control of symptoms of narcolepsy, we compared the potency of amphetamine isomers (D- and L-amphetamines) and a derivative (L-methamphetamine) on wakefulness and cataplexy. Their respective effects on these narcolepsy symptoms were then compared with their in vivo effects on extracellular DA levels in the caudate and NE levels in the frontal cortex during local drug perfusion in narcoleptic dogs. Polygraphic recordings demonstrated that D-amphetamine was about twice as potent as L-amphetamine, and was six times more potent than L-methamphetamine in increasing wakefulness and reducing slow-wave sleep. D-Amphetamine and L-amphetamine were equipotent in reducing rapid eye movement sleep and cataplexy, and L-methamphetamine was about half as potent as L- and D-amphetamines. D-Amphetamine was found to be more potent in increasing DA efflux than L-amphetamine, and L-methamphetamine was found to have little effect on DA efflux; there was no significant difference in the potencies of the three derivatives on NE efflux. The potencies of these amphetamines on wakefulness correlated well with DA, but not NE, efflux in the brain of narcoleptic dogs during local drug perfusion. Our current results further exemplify the importance of the DA system for the pharmacological control of electroencephalogram arousal and suggest that increased DA transmission mediates the wake-promoting effects of amphetamine-like stimulants.
View details for Web of Science ID 000089250800007
View details for PubMedID 10974428
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Dopamine D3 agonists into the substantia nigra aggravate cataplexy but do not modify sleep (vol 10, pg 3111, 1999)
NEUROREPORT
1999; 10 (17): 3717-3724
Abstract
We have recently demonstrated that local perfusion of dopaminergic D2/D3 agonists into the ventral tegmental area (VTA) significantly aggravates cataplexy and increases sleep in narcoleptic Dobermans. We further assessed the roles of the mesostriatal dopaminergic system and found that local perfusion of quinpirole and 7-OH-DPAT into the substantia nigra (SN) significantly aggravated cataplexy, while perfusion of a D2/D3 antagonist significantly reduced cataplexy. Neither a D1 agonist nor a D1 antagonist modified cataplexy. SN perfusion of quinpirole did not significantly modify sleep, while VTA perfusion significantly increased the drowsy state. Although autoregulation of the VTA and SN dopaminergic neurons are involved in the regulation of cataplexy, both structures have distinct roles for the regulation of sleep.
View details for Web of Science ID 000083934000001
View details for PubMedID 10619672
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Drug treatment of patients with insomnia and excessive daytime sleepiness - Pharmacokinetic considerations
CLINICAL PHARMACOKINETICS
1999; 37 (4): 305-330
Abstract
Insomnia and excessive daytime sleepiness (EDS) are frequently observed conditions in the general public. A national survey in the USA in 1979 indicated that 35% of American adults experience insomnia in the course of a year. The prevalence of EDS varies depending on the survey (0.3 to 13.3%), but a recent study stated that 2.4% of individuals reported that they continually fell asleep at work. These problems are often long term and negatively affect the individuals' quality of life. People with these sleep problems often have difficulties maintaining high levels of productivity at work or pursuing their daily activities; individuals with insomnia lack the feeling of being rested or refreshed in the morning and EDS is unavoidable in most cases. Behavioural therapy has been shown to be effective for many people affected with insomnia and EDS. However, pharmacological treatments using hypnosedatives and central nervous system (CNS) stimulants are usually necessary, and effective, for those with more severe cases. These compounds have thus been widely prescribed in clinical practice (e.g., 2.6% of all adults surveyed used medically prescribed hypnosedatives and 4.5% used over-the-counter drugs to promote sleep). The onset and duration of action of these hypnosedatives and CNS stimulant drugs are important factors to be considered when prescribing these compounds. These factors primarily depend on physicochemical properties (lipid solubility and protein binding), as well as the pharmacokinetic profile (absorption, distribution, elimination and clearance) of the compounds. Significant differences in profile exist amongst hypnosedatives and CNS stimulants, and these differences may account for the observed variations in clinical action and adverse effects during and after treatment. In this review, we will introduce recently obtained knowledge of the pharmacokinetics of hypnosedatives and CNS stimulants and their applications for patients affected with insomnia and EDS.
View details for Web of Science ID 000083428700003
View details for PubMedID 10554047
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Dopamine D-3 agonists into the substratia nigra aggravates cataplexy but does not modify sleep
NEUROREPORT
1999; 10 (14): 3111-3118
Abstract
We have recently demonstrated that local perfusion of dopaminergic D2/D3 agonists into the ventral tegmental area (VTA) significantly aggravates cataplexy and increases sleep in narcoleptic Dobermans. We further assessed the roles of the mesostriatal dopaminergic system and found that local perfusion of quinpirole and 7-OH-DPAT into the substantia nigra (SN) significantly aggravated cataplexy, while perfusion of a D2/D3 antagonist significantly reduced cataplexy. Neither a D1 agonist nor a D1 antagonist modified cataplexy. SN perfusion of quinpirole did not significantly modify sleep, while VTA perfusion significantly increased the drowsy state. Although autoregulation of the VTA and SN dopaminergic neurons are involved in the regulation of cataplexy, both structures have distinct roles for the regulation of sleep.
View details for Web of Science ID 000082865500046
View details for PubMedID 10549832
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The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene
CELL
1999; 98 (3): 365-376
Abstract
Narcolepsy is a disabling sleep disorder affecting humans and animals. It is characterized by daytime sleepiness, cataplexy, and striking transitions from wakefulness into rapid eye movement (REM) sleep. In this study, we used positional cloning to identify an autosomal recessive mutation responsible for this sleep disorder in a well-established canine model. We have determined that canine narcolepsy is caused by disruption of the hypocretin (orexin) receptor 2 gene (Hcrtr2). This result identifies hypocretins as major sleep-modulating neurotransmitters and opens novel potential therapeutic approaches for narcoleptic patients.
View details for Web of Science ID 000081950300011
View details for PubMedID 10458611
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Neuronal activity in the cholinoceptive basal forebrain of freely moving narcoleptic dobermans
NEUROREPORT
1998; 9 (16): 3653-3661
Abstract
Cholinergic stimulation in the basal forebrain (BF) triggers cataplexy in canine narcolepsy. Extracellular single unit recordings in the BF were carried out in freely moving narcoleptic dogs to study the neuronal mechanisms mediating cataplexy induction in the BF. Among the 64 recorded neurons, 12 were wake-active, three were slow wave sleep (SWS)-active, 17 were wake-/REM-active, 11 were REM sleep-active, three were cataplexy-active, and the other 18 were state-independent. Systemic administration of physostigmine, a cholinesterase inhibitor, induces status cataplecticus, decreases SWS and increases acetylcholine levels in the BF. Firing of most of the state-dependent neurons in the BF was significantly modified by physostigmine. Some of these neurons may thus mediate sleep stage changes or the effect on cataplexy observed after cholinergic stimulation in the BF.
View details for Web of Science ID 000077493400021
View details for PubMedID 9858375
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Development of cataplexy in genetically narcoleptic Dobermans
EXPERIMENTAL NEUROLOGY
1998; 152 (2): 292-302
Abstract
Forty-two genetically narcoleptic Doberman puppies [20 pure narcoleptic (N) puppies (from four narcoleptic x narcoleptic crosses) and 22 backcross narcoleptic (BN) puppies (from six narcoleptic x heterozygous crosses)] were systematically observed during the developmental period (4-24 weeks) to assess the age at onset and severity of cataplexy, a pathological manifestation of REM sleep atonia seen in narcolepsy. The mean age of onset of cataplexy was 9.69 +/- 1.15 weeks, with a median age of 7 weeks. The severity of cataplexy increased with age and reached a plateau at around 16-24 weeks. The effects of cross type (N vs BN) and sex on the development of cataplexy were analyzed. There was no difference in severity between N and BN puppies (P = 0.51). However, females had more severe cataplexy than males (P = 0.01), and this trend was preserved in five of the six litters that had both male and female puppies. These results suggest that the pathophysiological process in genetic canine narcolepsy emerges during the early developmental period and that it may involve a differential development in males and females. Furthermore, our results revealed that cataplexy onset corresponds to the emergence of adult-like REM sleep and to previously reported neuroanatomical and neurochemical abnormalities in canine narcolepsy.
View details for Web of Science ID 000075698200014
View details for PubMedID 9710528
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Cerebrospinal fluid prostaglandins and corticotropin releasing factor in schizophrenics and controls: relationship to sleep architecture
PSYCHIATRY RESEARCH
1998; 78 (3): 141-150
Abstract
Sleep abnormalities have been consistently observed in patients with schizophrenia. Elevated levels of corticotropin releasing factor (CRF) and prostaglandins (PGs) in the cerebrospinal fluid (CSF) of patients with schizophrenia have been reported, and these neurochemical substances, known to modulate sleep in experimental animals, may play a role in these sleep abnormalities. In this study, we measured PGD2, PGE2, PGF2alpha and CRF levels in the CSF of 14 unmedicated schizophrenic patients and 14 age- and sex-matched control subjects. Polysomnographic recordings were also carried out for each subject. As expected, the sleep of the schizophrenic subjects significantly differed from that of the controls; schizophrenic subjects had a longer sleep onset latency, slept less, spent fewer minutes in stage 2 sleep and had a lower sleep efficiency. We could not, however, detect any differences in CSF CRF and PG levels between normal and schizophrenic subjects, nor could we find any correlation between CSF variables and sleep parameters in the schizophrenic subjects and the non-psychiatric controls. These results do not favor the hypothesis of a role for CRF or PGs in the pathophysiology of sleep disturbances in schizophrenia.
View details for Web of Science ID 000074238900003
View details for PubMedID 9657418
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Neuropharmacological characterization of basal forebrain cholinergic stimulated cataplexy in narcoleptic canines
EXPERIMENTAL NEUROLOGY
1998; 151 (1): 89-104
Abstract
Basal forebrain (BF) cholinergic regulation of cataplexy was investigated in narcoleptic canines. Specific cholinergic agonists and antagonists, and excitatory or inhibitory amino acid neurotransmitter receptor agonists, were perfused through microdialysis probes implanted bilaterally in the BF of narcoleptic canines. Cataplexy was monitored using the food-elicited cataplexy test (FECT) and recordings of electroencephalogram, electrooculogram, and electromyogram. In narcoleptic canines, carbachol and oxotremorine (10(-5)-10(-3) M), but not McN-A-343 or nicotine (10(-4)-10(-3) M), produced a dose-dependent increase in cataplexy. In addition, N-methyl-d-aspartate (10(-4)-10(-3) M) and kainic acid (10(-5)-10(-4) M) did not have any effects, while muscimol (10(-3) M) produced a weak (P < 0.10) increase in cataplexy. In control canines, carbachol (10(-5)-10(-3) M), but not oxotremorine (10(-4)-10(-3) M), produced muscle atonia after the highest concentration in one of three animals. Carbachol (10(-3) M)-induced cataplexy in narcoleptic canines was blocked by equimolar perfusion with the muscarinic antagonists atropine, gallamine, and 4-DAMP but not pirenzepine. These findings indicate that carbachol-stimulated cataplexy in the BF of narcoleptic canines is mediated by M2, and perhaps M3, muscarinic receptors. The release of acetylcholine in the BF was also examined during FECT and non-FECT behavioral stimulation in narcoleptic and control canines. A significant increase in acetylcholine release was found in both narcoleptic and control BF during FECT stimulation. In contrast, simple motor activity and feeding, approximating that which occurs during an FECT, did not affect acetylcholine release in the BF of narcoleptic canines. These findings indicate that BF acetylcholine release is enhanced during learned emotion/reward associated behaviors in canines.
View details for Web of Science ID 000073593600008
View details for PubMedID 9582257
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Breeding history of the Stanford colony of narcoleptic dogs
VETERINARY RECORD
1998; 142 (2): 31-36
Abstract
Narcolepsy is a disabling sleep disorder of unknown aetiology. In humans, the disease is mostly sporadic, with a few familial cases having been reported. In 1973 a sporadic case of narcolepsy was reported in a poodle, and in 1975 familial cases of narcolepsy occurred in dobermanns. As with human narcoleptics, these narcoleptic dogs exhibited excessive daytime sleepiness and cataplexy. A colony of narcoleptic dogs was established at Stanford University in 1976 to study the pathophysiology of the disease. Between 1976 and 1995, a total of 669 animals of various breeds were born, of which 487 survived. Dobermanns accounted for 78 per cent of the total. The narcolepsy genotype in dobermanns had no significant influence on puppy mortality rate (numbers of stillborn and survival rate). The sex, maternal parity or the age of the sire or dam had no significant effect. The percentage of stillborn puppies increased from 6.1 per cent in outbred litters to 15.4 per cent in inbred litters (P = 0.10). Birth season also had a significant effect, and the highest survival rate (P = 0.02), and the lowest percentage of stillborn puppies (P = 0.09) occurred between April and June.
View details for Web of Science ID 000071662300006
View details for PubMedID 9481825
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Increased dopaminergic transmission mediates the wake-promoting effects of CNS stimulants.
Sleep research online : SRO
1998; 1 (1): 49-61
Abstract
Amphetamine-like stimulants are commonly used to treat sleepiness in narcolepsy. These compounds have little effect on rapid eye movement (REM) sleep-related symptoms such as cataplexy, and antidepressants (monoamine uptake inhibitors) are usually required to treat these symptoms. Although amphetamine-like stimulants and antidepressants enhance monoaminergic transmission, these compounds are non-selective for each monoamine, and the exact mechanisms mediating how these compounds induce wakefulness and modulate REM sleep are not known. In order to evaluate the relative importance of dopaminergic and noradrenergic transmission in the mediation of these effects, five dopamine (DA) uptake inhibitors (mazindol, GBR-12909, bupropion, nomifensine and amineptine), two norepinephrine (NE) uptake inhibitors (nisoxetine and desipramine), d-amphetamine, and modafinil, a non-amphetamine stimulant, were tested in control and narcoleptic canines. All stimulants and dopaminergic uptake inhibitors were found to dose-dependently increase wakefulness in control and narcoleptic animals. The in vivo potencies of DA uptake inhibitors and modafinil on wake significantly correlated with their in vitro affinities to the DA and not the NE transporter. DA uptake inhibitors also moderately reduced REM sleep, but this effect was most likely secondary to slow wave sleep (SWS) suppression, since selective DA uptake inhibitors reduced both REM sleep and SWS proportionally. In contrast, selective NE uptake inhibitors had little effect on wakefulness, but potently reduced REM sleep. These results suggest that presynaptic activation of DA transmission is critical for the pharmacological control of wakefulness, while that of the NE system is critical for REM sleep regulation. Our results also suggest that presynaptic activation of DA transmission is a key pharmacological property mediating the wake-promoting effects of currently available CNS stimulants.
View details for PubMedID 11382857
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Central administration of vitamin B-12 aggravates cataplexy in canine narcolepsy
NEUROREPORT
1997; 8 (18): 3861-3865
Abstract
Experimental evidence in canine narcolepsy suggests that central cholinergic systems are critically involved in the regulation of cataplexy, an abnormal manifestation of REM sleep atonia. In the current study, we found that intracerebroventricular perfusion of methyl-B12, (10(-5)-10(-2) M), significantly aggravated cataplexy and enhanced REM sleep in narcoleptic dogs. Choline, a direct precursor of acetylcholine, was also found to aggravate cataplexy, while cyano-B12, a vitamin B12 analog without methyl donating abilities, had no effect on cataplexy. Since both methyl-B12 and choline are reported to enhance acetylcholine synthesis, enhancement of the biosynthesis of acetylcholine may be involved in the effects observed in canine narcolepsy. Our results suggest that central administration of methyl-B12 has the potential to modulate both normal and pathological REM sleep.
View details for Web of Science ID 000071221500006
View details for PubMedID 9462456
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Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy
JOURNAL OF NEUROSCIENCE
1997; 17 (16): 6401-6408
Abstract
The therapeutic potential of thyrotropin-releasing hormone (TRH) and TRH analogs in narcolepsy, a sleep disorder characterized by abnormal rapid eye movement (REM) sleep and daytime sleepiness, was examined using the canine model. The effects of TRH and the biologically stable TRH analogs CG3703, CG3509, and TA0910 on daytime sleep and cataplexy, a symptom of abnormal REM sleep, were assessed using polysomnographic recordings and the food elicited cataplexy test (FECT), respectively. CG3703 (100 and 400 microg/kg, i.v.) and TA0910 (100 and 400 microg/kg, i.v.) significantly increased wakefulness and decreased sleep in narcoleptic canines, whereas TRH (400 and 1600 microg/kg, i.v.) had no significant effect. TRH (25-1600 microg/kg, i.v.) and all three TRH analogs, CG3703 (6. 25-400 microg/kg, i.v., and 0.25-16 mg/kg, p.o.), CG3509 (25-1600 microg/kg, i.v.), and TA0910 (25-1600 microg/kg, i.v.), significantly reduced cataplexy in canine narcolepsy. These compounds did not produce any significant side effects during behavioral assays, nor did they alter free T3 and T4 levels in serum even when used at doses that completely suppressed cataplexy. Although more work is needed to establish the mode of action of TRH analogs on alertness and REM sleep-related symptoms, our results suggest a possible therapeutic application for TRH analogs in human sleep disorders.
View details for Web of Science ID A1997XU78100037
View details for PubMedID 9236248
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Circadian distribution of rest/activity in narcoleptic and control dogs: Assessment with ambulatory activity monitoring
JOURNAL OF SLEEP RESEARCH
1997; 6 (2): 120-127
Abstract
Like human narcoleptics, narcoleptic dogs display cataplexy, fragmented sleep and excessive daytime sleepiness. Cataplexy in dogs can easily be quantified using a simple behavioural bioassay, the Food Elicited Cataplexy Test. In contrast, daytime sleepiness and fragmented sleep are more difficult to measure, as long-term, labour-intensive polygraphic recordings in surgically-implanted animals are needed. In the current study, 24-h rest/activity patterns in genetically narcoleptic, asymptomatic heterozygous and control Dobermans were compared using small sized ambulatory activity monitoring devices under 12-h light/dark conditions. Control and heterozygous dogs were found to be more active during the light period than during the dark period, thus demonstrating a clear 24-h rest/activity cycle. In contrast, narcoleptic dogs were relatively inactive during the light period and did not show a clear rest/activity pattern, a result similar to that of human narcoleptics. Considering the fact that narcoleptic dogs show shorter sleep latency and sleep significantly more during the daytime than control dogs, the decrease in activity in narcoleptic dogs during the daytime is most likely a reflection of increased daytime napping in these animals. Ambulatory activity monitoring may be a useful non-invasive method for future pharmacological and development studies in the narcoleptic canine model.
View details for Web of Science ID A1997XL41000007
View details for PubMedID 9377531
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Pharmacological aspects of human and canine narcolepsy
PROGRESS IN NEUROBIOLOGY
1997; 52 (1): 27-78
Abstract
Narcolepsy-cataplexy is a disabling neurological disorder that affects 1/2000 individuals. The main clinical features of narcolepsy, excessive daytime sleepiness and symptoms of abnormal REM sleep (cataplexy, sleep paralysis, hypnagogic hallucinations) are currently treated using amphetamine-like compounds or modafinil and antidepressants. Pharmacological research in the area is facilitated greatly by the existence of a canine model of the disorder. The mode of action of these compounds involves presynaptic activation of adrenergic transmission for the anticataplectic effects of antidepressant compounds and presynaptic activation of dopaminergic transmission for the EEG arousal effects of amphetamine-like stimulants. The mode of action of modafmil is still uncertain, and other neurochemical systems may offer interesting avenues for therapeutic development. Pharmacological and physiological studies using the canine model have identified primary neurochemical and neuroanatomical systems that underlie the expression of abnormal REM sleep and excessive sleepiness in narcolepsy. These involve mostly the pontine and basal forebrain cholinergic, the pontine adrenergic and the mesolimbic and mesocortical dopaminergic systems. These studies confirm a continuing need for basic research in both human and canine narcolepsy, and new treatments that act directly at the level of the primary defect in narcolepsy might be forthcoming.
View details for Web of Science ID A1997XC57300002
View details for PubMedID 9185233
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Mesopontine organization of cholinergic and catecholaminergic cell groups in the normal and narcoleptic dog
JOURNAL OF COMPARATIVE NEUROLOGY
1997; 379 (2): 185-197
Abstract
Canine narcolepsy is a unique experimental model of a human sleep disorder characterized by excessive daytime sleepiness and cataplexy. There is a consensus recognition of an imbalance between cholinergic and catecholaminergic systems in narcolepsy although the underlying mechanisms remain poorly understood. Possible substrates could be an abnormal organization, numbers and/or ratio of cholinergic to catecholaminergic cells in the brain of narcoleptic dogs. Therefore, we sought to characterize the corresponding neuronal populations in normal and narcoleptic dogs (Doberman Pinscher) by using choline acetyltransferase (ChAT), nicotinamide adenosine dinucleotide phosphate (NADPH)-diaphorase, tyrosine hydroxylase (TH), and dopamine beta-hydroxylase (DBH). Cholinergic cell groups were found in an area extending from the central to the gigantocellular tegmental field and the periventricular gray corresponding to the pedunculopontine tegmental nucleus (PPT), the laterodorsal tegmental nucleus (LDT), and the parabrachial nucleus. An almost perfect co-localization of ChAT and NADPH-diaphorase was also observed. Catecholaminergic cell groups detected included the ventral tegmental area, the substantia nigra, and the locus coeruleus nucleus (LC). The anatomical distribution of catecholaminergic neurons was unusual in the dog in two important aspects: i) TH- and/or DBH-immunoreactive neurons of the LC were found almost exclusively in the reticular formation and not within the periventricular gray, ii) very few, if any TH-positive neurons were found in the central gray and dorsal raphe. Quantitative analysis did not reveal any significant differences in the organization and the number of cells identified in the LDT, PPT, and LC of normal and narcoleptic dogs. Moreover, the cholinergic to catecholaminergic ratio was found identical in the two groups. In conclusion, the present results do not support the hypothesis that the neurochemical imbalance in narcolepsy could result from abnormal organization, numbers, or ratio of the corresponding neuronal populations.
View details for Web of Science ID A1997WL65800002
View details for PubMedID 9050784
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Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine
BRAIN RESEARCH
1996; 733 (1): 83-100
Abstract
Cataplexy in the narcoleptic canine may be modulated by systemic administration of monoaminergic compounds. In the present study, we have investigated the effects of monoaminergic drugs on cataplexy in narcoleptic canines when perfused locally via microdialysis probes in the amygdala, globus pallidus/putamen, basal forebrain, pontine reticular formation and ventral tegmental area of narcoleptic and control Doberman pinchers. Cataplexy was quantified using the Food-Elicited Cataplexy Test and analyzed by electroencephalogram, electroculogram and electromyogram. Local perfusion with the monoaminergic agonist quinpirole, 7-OH-DPAT and BHT-920, into the ventral tegmental area produced a dose-dependent increase in cataplexy without significantly reducing basal muscle tone. Perfusion with the antagonist raclopride in the same structure produced a moderate reduction in cataplexy. Local perfusion with quinpirole, 7-OH-DPAT and BHT-920 into the globus pallidus/putamen also produced an increase, while raclopride produced a decrease, in cataplexy in narcoleptic canines. In control animals, none of the above drugs produced cataplexy or muscle atonia when perfused into either the ventral tegmental area or the globus pallidus/putamen. Other monoaminergic drugs tested in these two brain areas; prazosin, yohimbine, amphetamine, SKF 38393 and SCH 23390 had no effects on cataplexy. Local perfusion with each of the above listed drugs had no effect on cataplexy in any of the other brain regions examined. These findings show that cataplexy may be regulated by D2/D3 dopaminergic receptors in the ventral tegmental area and perhaps the globus pallidus/ putamen. It is suggested that neurons in the mesolimbic dopamine system of narcoleptics are hypersensitive to dopaminergic autoreceptor agonists.
View details for Web of Science ID A1996VJ89400011
View details for PubMedID 8891251
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Thalidomide, a hypnotic with immune modulating properties, increases cataplexy in canine narcolepsy
NEUROREPORT
1996; 7 (12): 1881-1886
Abstract
Thalidomide is a sedative hypnotic that was widely used in the 1950s but was withdrawn due to its teratogenic properties. The compound has recently been reintroduced as an immune modulating agent. Thalidomide significantly aggravates canine cataplexy, a pathological manifestation of rapid eye movement (RFM) sleep atonia seen in narcolepsy. This compound also increases REM sleep and slow wave sleep in these animals. In vitro receptor binding and enzyme assays demonstrate that thalidomide does not bind to or enzymatically modulate the neurotransmitter systems reported to be involved in the regulation of cataplexy. Thalidomide may therefore affect cataplexy through its immune modulation properties. Further studies on the mechanisms of action of thalidomide should increase our understanding of the pathophysiology of this disabling disorder.
View details for Web of Science ID A1996VP15900002
View details for PubMedID 8905685
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Major histocompatibility class II molecules in the CNS: Increased microglial expression at the onset of narcolepsy in a canine model
JOURNAL OF NEUROSCIENCE
1996; 16 (15): 4588-4595
Abstract
Human narcolepsy is a neurological disorder known to be closely associated with HLA-DR2 and DQB1*0602. Because most autoimmune diseases are HLA-associated, a similar mechanism has been proposed for narcolepsy. However, neither systemic nor CNS evidence of an autoimmune abnormality has ever been reported. In this study, major histocompatibility (MHC) class I and class II expression was studied in the CNS of human and canine narcoleptics using immunohistochemistry and Northern analysis. Results indicated that canine narcolepsy is associated with a significant increase of MHC class II expression by the microglia. Moreover, the highest values were found between 3 and 8 months of age, strikingly concomitant to the development of narcolepsy in the canine model. In humans, class II expression was not found significantly different between control and narcoleptic subjects. This result could be explained by the old age of the subjects (69.86 +/- 5.31 and 68.36 +/- 4.74 years in narcoleptics and controls, respectively), because class II expression is significantly correlated with age in both humans and dogs. For the first time, this study demonstrated that the expression of MHC class II molecules in the CNS is age-dependent and that a consistent increase of their expression by the microglia might be critically involved in the development of narcolepsy.
View details for Web of Science ID A1996UX95500006
View details for PubMedID 8764647
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Thalidomide, immune modulation and narcolepsy
SLEEP
1996; 19 (2): 116-116
View details for Web of Science ID A1996UC74600005
View details for PubMedID 8855033
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Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs
SLEEP
1995; 18 (10): 817-826
Abstract
The effects of modafinil and amphetamine on daytime sleep (polysomnographic recordings) and cataplexy (the food-elicited cataplexy test) were compared using the narcoleptic canine model. Results indicate that both modafinil (5 and 10 mg/kg body weight i.v.) and amphetamine (100 and 200 micrograms/kg i.v.) increase wakefulness and reduce slow-wave sleep in control and narcoleptic dogs. In contrast, the results of cataplexy testing demonstrate that amphetamine (2.5-160 micrograms/kg i.v.), but not modafinil (0.125-8.0 mg/kg i.v.) significantly suppresses canine cataplexy. These results suggest that the pharmacological property of modafinil is distinct from amphetamine. Results of polysomnographic recordings also demonstrate that narcoleptic dogs slept significantly more during the daytime than control dogs and required very high doses (10 mg/kg i.v. modafinil; 200 micrograms/kg i.v. amphetamine) of stimulants to reduce their level of sleepiness to that of control dogs. This finding is consistent with the data collected in human narcolepsy and validates the use of this canine model for the screening of stimulant compounds.
View details for Web of Science ID A1995TQ23600001
View details for PubMedID 8746387
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MUSCLE ATONIA IS TRIGGERED BY CHOLINERGIC STIMULATION OF THE BASAL FOREBRAIN - IMPLICATION FOR THE PATHOPHYSIOLOGY OF CANINE NARCOLEPSY
JOURNAL OF NEUROSCIENCE
1995; 15 (7): 4806-4814
Abstract
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep-related symptoms, such as cataplexy. The exact pathophysiology underlying the disease is unknown but may involve central cholinergic systems. It is known that the brainstem cholinergic system is activated during REM sleep. Furthermore, REM sleep and REM sleep atonia similar to cataplexy can be triggered in normal and narcoleptic dogs by stimulating cholinergic receptors within the pontine brainstem. The pontine cholinergic system is, therefore, likely to play a role in triggering cataplexy and other REM-related abnormalities seen in narcolepsy. The other cholinergic system that could be involved in the pathophysiology of narcolepsy is located in the basal forebrain (BF). This system sends projections to the entire cerebral cortex. Since acetylcholine release in the cortex is increased both during REM and wake, the basocortical cholinergic system is believed to be involved in cortical desynchrony. In the current study, we analyzed the effect of cholinergic compounds injected into the forebrain structures of narcoleptic and control dogs. We found that carbachol (a cholinergic agonist) injected into the BF triggers cataplexy in narcoleptic dogs while it increases wakefulness in control dogs. Much higher doses of carbachol bilaterally injected in the BF were, however, shown to trigger muscle atonia even in control dogs. These results suggest that a cholinoceptive site in the BF is critically implicated in triggering muscle atonia and cataplexy. Together with similar results previously obtained in the pontine brainstem, it appears that a widespread hypersensitivity to cholinergic stimulation may be central to the pathophysiology of canine narcolepsy.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1995RJ66200008
View details for PubMedID 7623112
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EFFECT OF 5-HT1A RECEPTOR AGONISTS AND ANTAGONISTS ON CANINE CATAPLEXY
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
1995; 272 (3): 1170-1175
Abstract
Pharmacological studies using a canine model of narcolepsy have demonstrated that adrenergic rather than serotonergic or dopaminergic uptake inhibition is the primary mode of action of antidepressants on cataplexy, a pathological manifestation of rapid eye movement (REM) sleep atonia that occurs in narcolepsy. This result is in line with the known involvement of adrenergic systems in the regulation of REM sleep. However, the lack of anticataplectic effects of selective serotonergic compounds was puzzling as serotonergic neurons of the dorsal raphe nuclei are known to decrease activity during the REM sleep in a manner similar to the adrenergic neurons of the locus coeruleus. To further explore the role of serotonergic systems, we tested the effect on canine cataplexy of six 5-HT1A agonists and five 5-HT1A antagonists. Results indicate that 5-HT1A agonists significantly suppress cataplexy in correlation with their in vitro affinities to the canine central 5-HT1A receptors. Anticataplectic effects were, however, accompanied by various behavioral changes, such as flattened body posture, increased panting and agitation. In contrast, the selective 5-HT1A antagonist did not aggravate cataplexy, although a 5-HT1A antagonist was able to block the anticataplectic effect of a 5-HT1A agonist. These results suggest that the anticataplectic effects of 5-HT1A agonists are truly mediated by 5-HT1A receptor stimulation. It is, however, likely that anticataplectic effects occur due to the behavioral side effects rather than the direct involvement of this receptor subtype in the regulation of cataplexy. Further studies are therefore necessary to address the question of whether these 5-HT1A agonists hold promise in the pharmacological treatment of human cataplexy.
View details for Web of Science ID A1995QL99500028
View details for PubMedID 7891329
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NEUROPHARMACOLOGY AND NEUROCHEMISTRY OF CANINE NARCOLEPSY
4th International Conference on Narcolepsy
AMER SLEEP DISORDERS ASSOC. 1994: S84–S92
Abstract
It is believed that narcolepsy involves abnormalities of rapid eye movement (REM) sleep, especially of REM sleep atonia. Compelling evidence suggests that the regulation of REM sleep and REM sleep atonia involves a reciprocal interaction of cholinergic and monoaminergic systems. Using our canine model of narcolepsy and a pharmacological approach, we have previously demonstrated a similar interaction in the regulation of cataplexy. Global activation of cholinergic or monoaminergic transmission aggravates or suppresses canine cataplexy, respectively. We have also identified the subtypes of monoaminergic and cholinergic receptors specifically involved in this interaction. Cataplexy is aggravated by activation of the cholinergic system via M2 stimulation, as well as deactivation of the catecholaminergic systems by either blockade of postsynaptic alpha-1b receptors or stimulation of alpha-2 or D2 inhibitory autoreceptors. These pharmacological results correspond to previously identified neurochemical abnormalities in canine narcolepsy, such as significant increases in M2 receptors in the pons, alpha-1 receptors in the amygdala, alpha-2 receptors in the locus coeruleus and D2 receptors in the amygdala and nucleus accumbens, when compared to control animals. Using local perfusion of active compounds, we have further demonstrated that cholinoceptive sites in the pontine reticular formation, as well as in the basal forebrain, are involved in the regulation of cataplexy. Although the specific sites of action of the monoaminergic compounds remain unknown, the results of our pharmacological and neurochemical studies to date suggest that a widespread hyperactivity of cholinergic systems within the central nervous system together with a hypoactivity of catecholaminergic systems underlie the pathophysiology of narcolepsy.
View details for Web of Science ID A1994QD08100016
View details for PubMedID 7701206
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MODAFINIL BINDS TO THE DOPAMINE UPTAKE CARRIER SITE WITH LOW-AFFINITY
SLEEP
1994; 17 (5): 436-437
View details for Web of Science ID A1994PE28600006
View details for PubMedID 7991954
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CHOLINERGIC REGULATION OF CATAPLEXY IN CANINE NARCOLEPSY IN THE PONTINE RETICULAR-FORMATION IS MEDIATED BY M2 MUSCARINIC RECEPTORS
SLEEP
1994; 17 (5): 424-435
Abstract
Both rapid eye movement sleep and cataplexy in the narcoleptic canine have been shown to increase after both systemic and local administration of cholinergic agonists in the pontine reticular formation. Furthermore, binding studies indicate an increase in the number of M2 muscarinic receptors in the pontine reticular formation of narcoleptic canines. In the present study we have investigated the receptor subtypes involved in mediating the cholinergic stimulation of cataplexy, as defined by brief periods of hypotonia induced by emotions, within the pontine reticular formation of narcoleptic canines. Specific cholinergic and monoaminergic agonists and antagonists, and excitatory or inhibitory amino-acid neurotransmitter receptor agonists, were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of narcoleptic canines, and cataplexy was monitored using the Food-Elicited Cataplexy Test and recordings of electroencephalogram, electrooculogram and electromyogram. In narcoleptic canines, bilateral perfusion with oxotremorine (M2 muscarinic) (10(-5)-10(-3) M) in the pontine reticular formation produced a dose-dependent increase in cataplexy, which reached complete muscle atonia (status cataplecticus) during the highest concentration. In control canines bilateral perfusion with oxotremorine (10(-5)-10(-3) M) did not produce any cataplectic attacks, but did produce muscle atonia after the highest concentration. Bilateral perfusion with either McN-A-343 (M1 muscarinic) or nicotine (both 10(-5)-10(-3) M) did not have any effect on cataplexy in either narcoleptic or control canines. The increase in cataplexy in narcoleptic canines produced by local perfusion with carbachol (10(-4) M) followed by equimolar perfusion with a muscarinic antagonist was rapidly reversed by atropine (muscarinic) and gallamine (M2 muscarinic), partially reversed by 4-DAMP (M3/M1 muscarinic) and completely unaffected by pirenzepine (M1 muscarinic). Bilateral perfusion with excitatory, glutamatergic receptor agonists N-methyl-D-aspartate, AMPA (both at 10(-4)-10(-3) M) and kainic acid (10(-5)-10(-4) M) did not have any effect on cataplexy, whereas bilateral perfusion with the inhibitory GABAergic receptor agonist muscimol (10(-4)-10(-3) M) produced a moderate increase in cataplexy in the narcoleptic canines. Bilateral perfusion with numerous monoaminergic compounds, BHT-920 (alpha-2 agonist), yohimbine (alpha-2 antagonist), propranolol (beta antagonist) and prazosin (alpha-1 antagonist), did not have any effect on cataplexy. These findings demonstrate that cholinergic regulation of cataplexy in the narcoleptic canine at the level of the pontine reticular formation is mediated by M2, and possibly M3, muscarinic receptors. The effects of muscimol indicate that the stimulation of cataplexy might be elicited by local neuronal inhibition.
View details for Web of Science ID A1994PE28600005
View details for PubMedID 7991953
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CHOLINERGIC MECHANISMS IN CANINE NARCOLEPSY .1. MODULATION OF CATAPLEXY VIA LOCAL-DRUG ADMINISTRATION INTO THE PONTINE RETICULAR-FORMATION
NEUROSCIENCE
1994; 59 (3): 511-522
Abstract
Cataplexy in the narcoleptic canine has been shown to increase after systemic administration of cholinergic agonists. Furthermore, the number of cholinergic receptors in the pontine reticular formation of narcoleptic canines is significantly elevated. In the present study we have investigated the effects of cholinergic drugs administered directly into the pontine reticular formation on cataplexy, as defined by brief episodes of hypotonia induced by emotions, in narcoleptic canines. Carbachol and atropine were perfused through microdialysis probes implanted bilaterally in the pontine reticular formation of freely moving, narcoleptic and control Doberman pinschers. Cataplexy was quantified using the Food-Elicited Cataplexy Test, and analysed using recordings of electroencephalogram, electrooculogram and electromyogram. Cataplexy was characterized by a desynchronized electroencephalogram and a drop in electromyogram and electrooculogram activity. In narcoleptic canines, both unilateral and bilateral carbachol (10(-5) to 10(-3) M) produced a dose-dependent increase in cataplexy, which resulted in complete muscle tone suppression at the highest concentration. In control canines, neither bilateral nor unilateral carbachol (10(-5) to 10(-3) M) produced cataplexy, although bilateral carbachol, did produce muscle atonia at the highest dose (10(-3)). The increase in cataplexy after bilateral carbachol (10(-4) M) was rapidly reversed when the perfusion medium was switched to one containing atropine (10(-4) M). Bilateral atropine (10(-3) to 10(-2) M) alone did not produce any significant effects on cataplexy in narcoleptic canines; however, bilateral atropine (10(-2) M) did reduce the increase in cataplexy produced by systemic administration of physostigmine (0.05 mg/kg, i.v.). These findings demonstrate that cataplexy in narcoleptic canines can be stimulated by applying cholinergic agonists directly into the pontine reticular formation. The ability of atropine to inhibit locally and systemically stimulated cataplexy indicates that the pontine reticular formation is a critical component in cholinergic stimulation of cataplexy. Therefore, it is suggested that the pontine reticular formation plays a significant role in the cholinergic regulation of narcolepsy.
View details for Web of Science ID A1994NF79800003
View details for PubMedID 8008205
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DESMETHYL METABOLITES OF SEROTONERGIC UPTAKE INHIBITORS ARE MORE POTENT FOR SUPPRESSING CANINE CATAPLEXY THAN THEIR PARENT COMPOUNDS
SLEEP
1993; 16 (8): 706-712
Abstract
Our series of pharmacological studies on canine narcolepsy has suggested that the adrenergic systems are more critically involved in the regulation of cataplexy than the serotonergic and dopaminergic systems. This, however, is an apparent contradiction to data obtained in human patients, which show that chronic oral administration of serotonergic uptake inhibitors, such as clomipramine, zimelidine and fluoxetine, is effective in reducing cataplexy. To explore this discrepancy, we have assessed the anticataplectic effects of various serotonergic uptake inhibitors and their active desmethyl metabolites on canine cataplexy. We found that the anticataplectic effect of the desmethyl metabolites, which are usually more potent for in vitro adrenergic uptake inhibition, was more potent and developed more rapidly than the effect of the parent compounds. Furthermore, the anticataplectic potency was positively correlated to the adrenergic uptake inhibition and was negatively correlated with serotonergic uptake inhibition among the 10 compounds tested. These results are consistent with our hypothesis of a preferential involvement of the adrenergic system in the control of cataplexy. Our results also suggest that the anticataplectic effect of "selective" serotonergic uptake inhibitors in human narcolepsy might be mediated by their less selective active metabolites.
View details for Web of Science ID A1993MV96900004
View details for PubMedID 8165384
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CANINE CATAPLEXY IS PREFERENTIALLY CONTROLLED BY ADRENERGIC-MECHANISMS - EVIDENCE USING MONOAMINE SELECTIVE UPTAKE INHIBITORS AND RELEASE ENHANCERS
PSYCHOPHARMACOLOGY
1993; 113 (1): 76-82
Abstract
Narcolepsy is currently treated with anti-depressants to control REM-related symptoms such as cataplexy and with amphetamine-like stimulants for the management of sleepiness. Both stimulant and antidepressant drugs presynaptically enhance monoaminergic transmission but both classes of compounds lack pharmacological specificity. In order to determine which monoamine is selectively involved in the therapeutic effect of these compounds, we examined the effects of selective monoamine uptake inhibitors and release enhancers on cataplexy using a canine model of the human disorder. A total of 14 compounds acting on the adrenergic (desipramine, nisoxetine, nortriptyline, tomoxetine, viloxazine), serotoninergic (fenfluramine, fluoxetine, indalpine, paroxetine, zimelidine) and dopaminergic (amfonelic acid, amineptine, bupropion, GBR 12909) systems were tested. Some additional compounds interesting clinically but with less pharmacological selectivity, i.e., cocaine, dextroamphetamine, methylphenidate, nomifensine and pemoline, were also included in the study. All compounds affecting noradrenergic transmission completely suppressed canine cataplexy at low doses in all dogs tested, whereas compounds which predominantly modified serotoninergic and dopaminergic transmission were either inactive or partially active at high doses. Our results demonstrate the preferential involvement of adrenergic systems in the control of cataplexy and, presumably, REM sleep atonia. Our findings also demonstrate that canine narcolepsy is a useful tool in assessing the pharmacological specificity of antidepressant drugs.
View details for Web of Science ID A1993MG37200013
View details for PubMedID 7862832
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FURTHER CHARACTERIZATION OF THE ALPHA-1 RECEPTOR SUBTYPE INVOLVED IN THE CONTROL OF CATAPLEXY IN CANINE NARCOLEPSY
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
1993; 264 (3): 1079-1084
Abstract
We have demonstrated previously that central noradrenergic mechanisms, especially postsynaptic alpha-1 receptors, are critically involved in the regulation of cataplexy, a pathological manifestation of rapid eye movement sleep atonia in narcolepsy. However, it has been shown recently that alpha-1 receptors constitute a heterogeneous population of binding sites, which is encoded by several distinct genes. In light of these findings, we investigated the possibility that the effect of alpha-1 compounds on cataplexy found in our previous study is mediated more specifically by certain alpha-1 receptor subtypes than by other subtypes. We therefore examined the effects of eight selective alpha-1 antagonists and five agonists on canine cataplexy and compared these with the affinities of the same compounds for the canine central alpha-1a and alpha-1b subtypes. The affinities of the compounds for the alpha-1 receptor subtypes were assessed by using [3H]prazosin receptor binding in combination with a 5-methylurapidil (an alpha-1a selective ligand) mask. Six of the eight alpha-1 antagonists tested exacerbated canine cataplexy, whereas all five agonists tested suppressed cataplexy. Furthermore, the potency (ED50 values) of the compounds on cataplexy significantly correlated with the affinity of the compounds for the alpha-1b binding site. These results are consistent with our earlier implication of the alpha-1 receptor mechanisms in the control of cataplexy and further suggest a specific involvement of the alpha-1b receptor subtype in these mechanisms.
View details for Web of Science ID A1993KT84600009
View details for PubMedID 8095546
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HETEROZYGOSITY AT THE CANARC-1 LOCUS CAN CONFER SUSCEPTIBILITY FOR NARCOLEPSY - INDUCTION OF CATAPLEXY IN HETEROZYGOUS ASYMPTOMATIC DOGS AFTER ADMINISTRATION OF A COMBINATION OF DRUGS ACTING ON MONOAMINERGIC AND CHOLINERGIC SYSTEMS
JOURNAL OF NEUROSCIENCE
1993; 13 (3): 1057-1064
Abstract
Narcolepsy is a genetically determined disorder of sleep characterized by excessive daytime sleepiness and abnormal manifestations of REM sleep that affects both humans and animals. Although its exact pathophysiologic mechanisms remain undetermined, recent experiments have demonstrated that in both humans and canines, susceptibility genes are linked with immune-related genes. A striking difference, however, is that the genes thought to be involved in the human pathology are autosomal dominant, whereas canine narcolepsy in Dobermans is transmitted as a single autosomal recessive gene with full penetrance (canarc-1). In this study, we have examined the development of narcoleptic symptoms in homozygous narcoleptic, heterozygous, and control Dobermans. Animals were behaviorally observed until 5 months of age and then treated at weekly intervals with cataplexy-inducing compounds that act on cholinergic or monoaminergic systems (alone and in combination). Our data indicate that cataplexy can be induced in 6-month-old asymptomatic heterozygous animals, but not in control canines, with a combination of drugs that act on the monoaminergic and cholinergic systems. This demonstrates that disease susceptibility may be carried by heterozygosity at the canarc-1 locus. Our data further suggest that cataplexy, a model of REM sleep atonia, is centrally regulated by a balance of activity between cholinergic and monoaminergic neurons.
View details for Web of Science ID A1993KP71100016
View details for PubMedID 8095066
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SERUM PROLACTIN RESPONSE TO A D2 ANTAGONIST IN NARCOLEPTIC AND CONTROL CANINES
SLEEP
1992; 15 (5): 474-475
View details for Web of Science ID A1992JT08400014
View details for PubMedID 1455131
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STRATEGIES FOR THE DEVELOPMENT OF NEW TREATMENTS IN SLEEP DISORDER MEDICINE
WORKSHOP ON TARGET RECEPTORS FOR ANXIOLYTICS AND HYPNOTICS : FROM MOLECULAR PHARMACOLOGY TO THERAPEUTICS
KARGER. 1992: 129–150
View details for Web of Science ID A1992BW57Z00015
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EFFECTS OF SDZ NVI-085, A PUTATIVE SUBTYPE-SELECTIVE ALPHA-1-AGONIST, ON CANINE CATAPLEXY, A DISORDER OF RAPID EYE-MOVEMENT SLEEP
EUROPEAN JOURNAL OF PHARMACOLOGY
1991; 205 (1): 11-16
Abstract
Canine narcolepsy is an animal model of the human rapid eye movement sleep disorder. Dogs exhibit bouts of sleep attacks and muscle atonia (cataplexy) that are induced by emotions and thought to be abnormal rapid eye movement sleep episodes. We have previously demonstrated that cataplexy is strongly inhibited by increases in noradrenergic activity. This effect is mediated through central alpha 1-adrenoceptors, presumably of the alpha 1B subtype. In this study, we demonstrate with the canine model that SDZ NVI-085, a new compound with alerting effects, is a potent anticataplectic agent that may act through stimulation of an alpha 1-adrenoceptor subtype.
View details for Web of Science ID A1991GU07700003
View details for PubMedID 1687464
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DOPAMINE-D2 MECHANISMS IN CANINE NARCOLEPSY
JOURNAL OF NEUROSCIENCE
1991; 11 (9): 2666-2671
Abstract
Narcolepsy is a sleep disorder characterized by abnormal manifestations of rapid-eye-movement (REM) sleep and excessive daytime sleepiness. Using a canine model of the disease, we found that central D2 antagonists suppressed cataplexy, a form of REM-sleep atonia occurring in narcolepsy, whereas this symptom was aggravated by D2 agonists. The effect on cataplexy was stereospecific for the S(-) enantiomer of sulpiride (a D2 antagonist) and the R(+) enantiomer of 3-PPP (a D2 agonist). There was also a significant correlation between the in vivo pharmacological potency and in vitro drug affinity for D2 receptors (but not for D1 and alpha 2 receptors) among the seven central D2 antagonists tested. Selective D1 compounds were also tested; however, the results were inconsistent because both antagonists and agonists generally suppressed cataplexy. Our current results demonstrate that central D2-type receptors are critically involved in the control of cataplexy and REM sleep. Furthermore, the finding that small doses of D2 antagonists suppressed cataplexy and induced behavioral excitation, while small doses of D2 agonists aggravated cataplexy and induced sedation, suggests that this effect is mediated presynaptically. However, considering the fact that selective dopamine reuptake inhibitors did not modify cataplexy and that our previous pharmacological results demonstrated a preferential involvement of the noradrenergic system in the control of cataplexy, we believe that the effect of D2 compounds on cataplexy is mediated secondarily via the noradrenergic systems.
View details for Web of Science ID A1991GE83100004
View details for PubMedID 1831837
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PLATELET ALPHA-2 ADRENOCEPTORS IN HUMAN AND CANINE NARCOLEPSY
BIOLOGICAL PSYCHIATRY
1991; 29 (4): 376-382
Abstract
We have recently established that canine narcolepsy (an autosomal recessive genetic model of the human disorder) is dramatically improved by treatment with alpha 2 antagonists such as yohimbine (Nishino et al: J Pharmacol Exp Ther 253:1145-1152, 1990). To further investigate the role of alpha 2 adrenoceptors in narcolepsy, receptors labeled with [3H] yohimbine were examined on platelets from human and canine narcoleptic subjects. Twenty-eight Doberman pinschers were studied, 7 controls (C), 7 heterozygous (Hz), and 14 narcoleptics (N) (age and sex matched), including eight animals born in a backcross setting (narcoleptic x heterozygous; 5 narcoleptics and 3 heterozygous). The Kd and Bmax of each group respectively, were as follows: C, Kd = 2.86 +/- 0.76 nmol/L, Bmax = 295.78 +/- 31.89 fmol/mg protein; Hz, Kd = 2.06 +/- 0.23 nmol/L, Bmax = 307.02 +/- 22.21 fmol/mg protein; and N, Kd = 2.72 +/- 0.45 nmol/L, Bmax = 267.52 +/- 19.47 fmol/mg protein. No statistical differences were found between groups using nonparametric (Kruskall-Wallis) statistical procedures, and there were no correlations between any binding parameter and symptom severity within the narcoleptic group. Platelet alpha 2 receptor affinity and density also did not differ between narcoleptic and heterozygous dogs in the backcross litter (N [n = 5], Kd = 1.94 +/- 0.59 nmol/L, Bmax = 290.6 +/- 64.7 fmol/mg protein; Hz [n = 3], Kd = 2.83 +/- 0.47 nmol/L, Bmax = 294.2 +/- 42.9 fmol/mg protein). Fourteen human subjects, seven control and seven narcoleptic patients (age and sex matched), were included in the study.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1991EZ69000008
View details for PubMedID 1645207
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PROSTAGLANDIN-E2 LEVELS IN CEREBROSPINAL-FLUID OF NORMAL AND NARCOLEPTIC DOGS
BIOLOGICAL PSYCHIATRY
1990; 28 (10): 904-910
Abstract
It has been shown that endogenous prostaglandin D2 and prostaglandin E2 (PGE2) are involved in sleep-wake regulation. Our recent experimental result that exogenously administered PGE2 significantly reduces canine cataplexy (a pathological equivalent of rapid-eye-movement sleep atonia and a symptom of narcolepsy) suggests that PGE2 is involved in the pathophysiology of canine narcolepsy. In order to further investigate the role of prostaglandins (PGs) in this disorder, PG levels in cerebrospinal fluid (CSF) of genetically homozygous narcoleptic, heterozygous (unaffected), and control Doberman pinschers were studied. PGE2 levels were measured by direct radioimmunoassay (RIA) and after high-grade purification using PG affinity columns and high-performance liquid chromatography. PGD2 and PGF2 alpha levels were measured by RIA after high-grade purification. There was no significant difference in PGE2 levels between homozygous narcoleptic and heterozygous or controls dogs, and PGD2 and PGF2 alpha levels were undetectable in most cases. Our results do not favor the hypothesis that central PGE2 levels are modified in canine narcolepsy, assuming that PGE2 levels in cisternal CSF properly reflect PGE2 production in the brain.
View details for Web of Science ID A1990EJ24100006
View details for PubMedID 2268692
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EFFECTS OF CENTRAL ALPHA-2 ADRENERGIC COMPOUNDS ON CANINE NARCOLEPSY, A DISORDER OF RAPID EYE-MOVEMENT SLEEP
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
1990; 253 (3): 1145-1152
Abstract
Recent experiments have demonstrated that pharmacological activation of central noradrenergic systems by monoaminergic stimulators or uptake blockers or through the stimulation of alpha-1 adrenergic receptors improved cataplexy, a major symptom of narcolepsy. In order to further the understanding of the control of cataplexy by noradrenergic mechanisms, the involvement of central alpha-2 adrenoceptors was examined in genetically narcoleptic Doberman pinschers using in vivo pharmacology. Yohimbine (1.5-96.0 micrograms/kg i.v.) and seven other selective and centrally acting alpha-2 adrenoceptor antagonists (rauwolscine: 1.5-96 micrograms/kg i.v.; atipemazole: 1.5-96 micrograms/kg i.v.; Wy-25309: 1.5-386 micrograms/kg i.v.; CGS-7525A: 1.5-386 micrograms/kg i.v.; idazoxan, 6-1536 micrograms/kg i.v.; piperoxan, 6-1536 micrograms/kg i.v.; and mianserin, 6-1536 micrograms/kg i.v.) significantly suppressed cataplexy. The alpha-2 mediation of this effect was demonstrated by a close correlation between drug affinities (Ki) toward the alpha-2 site (defined using [3H]yohimbine in canine cortex) and the ability of these drugs to reduce cataplexy [ED50 in nanomoles per kilogram i.v.) (r2 = 0.71, n = 8, P less than .01). The effects of six centrally acting alpha-2 agonists on canine cataplexy were also examined and two groups of compounds were distinguished on the basis of their pharmacological profile. Classical alpha-2 agonists such as clonidine (0.0625-4.0 micrograms/kg i.v.), p-aminoclonidine (0.0625-4.0 micrograms/kg i.v.) and guanfacine (0.0625-4.0 micrograms/kg i.v.) had no effect on cataplexy whereas BHT-920 (0.01875-3.0 micrograms/kg i.v.), BHT-933 (16.0-258 micrograms/kg i.v.) and xylazine (16.0-258 micrograms/kg i.v.) dramatically aggravated cataplexy.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1990DK70200035
View details for PubMedID 1972749
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NORADRENERGIC AND CHOLINERGIC CONTROL OF CATAPLEXY - PHARMACOLOGICAL EVIDENCE
2ND INTERNATIONAL SYMP ON ENDOGENOUS SLEEP FACTORS
S P B ACADEMIC PUBL. 1990: 203–215
View details for Web of Science ID A1990BT19L00021
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EFFECTS OF INTRAVENOUS ADMINISTRATION OF PROSTAGLANDINS ON CANINE NARCOLEPSY
2ND INTERNATIONAL SYMP ON ENDOGENOUS SLEEP FACTORS
S P B ACADEMIC PUBL. 1990: 77–83
View details for Web of Science ID A1990BT19L00009
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CANINE NARCOLEPSY IS ASSOCIATED WITH AN ELEVATED NUMBER OF ALPHA-2-RECEPTORS IN THE LOCUS COERULEUS
BRAIN RESEARCH
1989; 500 (1-2): 209-214
Abstract
alpha 2-Receptors in the canine brain were pharmacologically characterized using [3H]yohimbine binding. Competition studies revealed a single class of binding sites in frontal cortex but two distinct subtypes in nucleus caudatus. The role of central alpha 2-receptors in narcolepsy was investigated in 5 normal and 5 narcoleptic Doberman pinschers. Scatchard analysis of [3H]yohimbine binding in different brain areas revealed an increase in the number of alpha 2-binding sites limited to the locus coeruleus. This suggests that altered autoinhibition of norepinephrine release may be associated with the narcoleptic symptomatology.
View details for Web of Science ID A1989AX91400023
View details for PubMedID 2557958
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CENTRAL ALPHA-1 ADRENOCEPTOR SUBTYPES IN NARCOLEPSY-CATAPLEXY - A DISORDER OF REM-SLEEP
BRAIN RESEARCH
1989; 490 (1): 186-191
Abstract
The present study suggests the specific involvement within the central nervous system of an alpha 1 adrenoceptor subtype in a behavior, the control of cataplexy, a pathological analogue of rapid eye movement (REM) sleep atonia. Experiments have shown that prazosin, an alpha 1 antagonist, dramatically aggravates canine narcolepsy-cataplexy through a central mechanism, and that [3H]prazosin binding sites are increased in the amygdala of narcoleptic dogs. However, the corresponding Scatchard plots were curvilinear and best fit was obtained with a two-site model, suggesting the existence of two [3H]prazosin binding sites. These two sites (high and low affinity [3H]prazosin binding sites) met the criteria for authentic receptors and were respectively very similar to the alpha 1a and alpha 1b (high and low affinity for WB4101, respectively) subtypes recently described in the rat and rabbit. Our results of in vivo pharmacology and in vitro [3H]prazosin binding in canine narcolepsy now clearly implicate the low affinity [3H]prazosin binding site (alpha 1b) in canine narcolepsy: (1) Prazosin, an alpha 1 antagonist with similar affinity for both subtypes, was much more potent in increasing cataplexy than WB4101, a compound with more affinity for the alpha 1a receptor. (2) Chlorethylclonidine and phenoxybenzamine, two irreversible blockers of the alpha 1 receptors with more affinity for the alpha 1b receptors, aggravate cataplexy for up to two weeks. (3) The alpha 1 receptor upregulation previously reported by our group in the amygdala of narcoleptic dogs was due to a selective increase in the low affinity [3H]prazosin binding sites. A role for noradrenaline in REM sleep regulation has been suspected for many years, but has never been clearly elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1989AC86100027
View details for PubMedID 2569353
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PROSTAGLANDIN-E2 AND ITS METHYL-ESTER REDUCE CATAPLEXY IN CANINE NARCOLEPSY
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
1989; 86 (7): 2483-2487
Abstract
The effects of intravenous administration of prostaglandins (PGs) were investigated in genetically narcoleptic Doberman pinschers. The treatment of narcoleptic dogs with PGE2 and PGE2 methyl ester, but not PGD2 and PGD2 methyl ester, induced a dose-dependent reduction of canine cataplexy, a dissociated manifestation of rapid-eye-movement sleep. The effect was specific and not associated with any change in other behavior. Furthermore, the effect was long-lasting (up to 2 hr) and could not be explained by the acute cardiovascular changes seen after intravenous PG administration. PGE2 methyl ester, a lipophilic derivative of PGE2 with more central penetration than PGE2, was 4 times more potent than PGE2. These results indicate that PGE2 modifies cataplexy through a central effect and suggest that this prostaglandin may play a role in rapid-eye-movement sleep regulation.
View details for Web of Science ID A1989U042300075
View details for PubMedID 2928344