I am a happy camper, searching for roads less traveled that end in wilderness trails.
Neuroscience Program Executive, Stanford Medical School (1997 - 2005)
Neuroscience Admissions Panel, Stanford Medical School (2000 - 2005)
NIH Study Section - Adjunct, NIH (2004 - 2012)
Neuroscience Subcommittee, Amer Soc Anesthesiology (2006 - 2013)
Environmental Health & Safety, Stanford University (2006 - 2009)
Committee on Graduate Studies, Stanford University (2008 - 2011)
Faculty Senate, Stanford Medical School (2008 - 2017)
NIH SAT Study Section, NIH (2013 - 2020)
File Reviewer, Stanford Neuroscience PhD Program (2017 - Present)
Associate Editor, Journal of Neurophysiology (2020 - Present)
Editorial Board, Trends in Anaesthesia and Critical Care (2020 - Present)
Associate Editor, Anesthesia & Analgesia (2022 - Present)
Honors & Awards
Allen V. Cox Medal, Stanford University (2004)
Top 100 Citations, Anesthesia & Analgesia (2005)
Top 10 % Reveiwer, Publons (publons.com) (2015)
Top 5 % of Reviews, Faculty of 1000 (2010 - 2015)
Elmer Zsigmond Award, International Society for Anaesthetic Pharmacology (2017)
Boards, Advisory Committees, Professional Organizations
Subcommittee Member, American Society of Anesthesiology (2005 - 2013)
Member, Society for Neuroscience (1985 - Present)
Member, Association of University Anesthesiologists (1998 - Present)
Member, International Society for Anaesthetic Pharmacology (2013 - Present)
BSc MSc PhD, University of Calgary, Alberta, Neuropharmacology (1987)
Community and International Work
KQED, San Francisco
Opportunities for Student Involvement
Sierra Club since 1987
Opportunities for Student Involvement
Amnesty International since 1996
Opportunities for Student Involvement
Wilderness Foundation since 1991
Opportunities for Student Involvement
Assessment, Testing and Measurement
Brain and Learning Sciences
Current Research and Scholarly Interests
Cellular, synaptic and molecular mechanisms of action of central nervous system drugs; especially barbiturates, opiates, anesthetics, abused inhalants and new experimental drugs. We use electrophysiological recording techniques and selective pharmacological probes, in hippocampal and cortical brain slices, to investigate sites and mechanisms of action for CNS active agents. The long-term goal of our studies is to provide physiological background information required for the rational design of safer and more effective drugs for anesthesia. Our recent studies have focussed on anesthetic effects at glutamate and GABA-mediated synapses as important targets for the CNS depressant effects of these agents. Depressed glutamate-mediated excitatory neurotransmission appears to be a common effect produced by most general anesthetics. We are currently studying agent specific actions at AMPA and NMDA glutamate receptor subtypes. Enhanced GABA-mediated inhibitory neurotransmission also appears to play an important role for many anesthetics. Anesthetics act at both pre- and post-synaptic sites to alter neurotransmission in higher brain centers. Thus, discrete synaptic targets could provide fruitful avenues for the development of safer and more effective therapeutic agents for analgesia and anesthesia.
Independent Studies (10)
- Directed Reading in Anesthesiology
ANES 299 (Aut, Win, Spr, Sum)
- Directed Reading in Neurosciences
NEPR 299 (Sum)
- Early Clinical Experience in Anesthesia
ANES 280 (Aut, Win, Spr, Sum)
- Graduate Research
ANES 399 (Aut, Win, Spr, Sum)
- Graduate Research
NEPR 399 (Sum)
HUMBIO 194 (Spr)
- Medical Scholars Research
ANES 370 (Aut, Win, Spr, Sum)
- Out-of-Department Undergraduate Research
BIO 199X (Sum)
- Research in Human Biology
HUMBIO 193 (Aut, Win)
- Undergraduate Research
ANES 199 (Win, Spr, Sum)
- Directed Reading in Anesthesiology
Doctoral Dissertation Reader (AC)
Missing Puzzle Pieces in Dementia Research: HCN Channels and Theta Oscillations.
Aging and disease
Increasing evidence indicates a role of hyperpolarization activated cation (HCN) channels in controlling the resting membrane potential, pacemaker activity, memory formation, sleep, and arousal. Their disfunction may be associated with the development of epilepsy and age-related memory decline. Neuronal hyperexcitability involved in epileptogenesis and EEG desynchronization occur in the course of dementia in human Alzheimer's Disease (AD) and animal models, nevertheless the underlying ionic and cellular mechanisms of these effects are not well understood. Some suggest that theta rhythms involved in memory formation could be used as a marker of memory disturbances in the course of neurogenerative diseases, including AD. This review focusses on the interplay between hyperpolarization HCN channels, theta oscillations, memory formation and their role(s) in dementias, including AD. While individually, each of these factors have been linked to each other with strong supportive evidence, we hope here to expand this linkage to a more inclusive picture. Thus, HCN channels could provide a molecular target for developing new therapeutic agents for preventing and/or treating dementia.
View details for DOI 10.14336/AD.2023.0607
View details for PubMedID 37450922
Electronic Energy Migration in Microtubules.
ACS central science
2023; 9 (3): 352-361
The repeating arrangement of tubulin dimers confers great mechanical strength to microtubules, which are used as scaffolds for intracellular macromolecular transport in cells and exploited in biohybrid devices. The crystalline order in a microtubule, with lattice constants short enough to allow energy transfer between amino acid chromophores, is similar to synthetic structures designed for light harvesting. After photoexcitation, can these amino acid chromophores transfer excitation energy along the microtubule like a natural or artificial light-harvesting system? Here, we use tryptophan autofluorescence lifetimes to probe energy hopping between aromatic residues in tubulin and microtubules. By studying how the quencher concentration alters tryptophan autofluorescence lifetimes, we demonstrate that electronic energy can diffuse over 6.6 nm in microtubules. We discover that while diffusion lengths are influenced by tubulin polymerization state (free tubulin versus tubulin in the microtubule lattice), they are not significantly altered by the average number of protofilaments (13 versus 14). We also demonstrate that the presence of the anesthetics etomidate and isoflurane reduce exciton diffusion. Energy transport as explained by conventional Förster theory (accommodating for interactions between tryptophan and tyrosine residues) does not sufficiently explain our observations. Our studies indicate that microtubules are, unexpectedly, effective light harvesters.
View details for DOI 10.1021/acscentsci.2c01114
View details for PubMedID 36968538
View details for PubMedCentralID PMC10037452
Consciousness and inward electromagnetic field interactions.
Frontiers in human neuroscience
2022; 16: 1032339
Electromagnetic field (EMF) theories of mind/brain integration have been proposed to explain brain function for over seventy years. Interest in this theory continues to this day because it explains mind-brain integration and it offers a simple solution to the "binding problem" of our unified conscious experience. Thus, it addresses at least in part the "hard problem" of consciousness. EMFs are easily measured and many corelates have been noted for field activity; associated with loss and recovery of consciousness, sensory perceptions, and behavior. Unfortunately, the theory was challenged early on by experiments that were thought to have ruled out a role of EMFs in brain activity, and the field of neuroscience has since marginalized EMF theories. Here I explain why early evidence against EMFs contributing to consciousness was misinterpreted and offer an alternative view to help direct future research.
View details for DOI 10.3389/fnhum.2022.1032339
View details for PubMedID 36466618
View details for PubMedCentralID PMC9714613
Lamotrigine Attenuates Neuronal Excitability, Depresses GABA Synaptic Inhibition, and Modulates Theta Rhythms in Rat Hippocampus.
International journal of molecular sciences
1800; 22 (24)
Theta oscillations generated in hippocampal (HPC) and cortical neuronal networks are involved in various aspects of brain function, including sensorimotor integration, movement planning, memory formation and attention. Disruptions of theta rhythms are present in individuals with brain disorders, including epilepsy and Alzheimer's disease. Theta rhythm generation involves a specific interplay between cellular (ion channel) and network (synaptic) mechanisms. HCN channels are theta modulators, and several medications are known to enhance their activity. We investigated how different doses of lamotrigine (LTG), an HCN channel modulator, and antiepileptic and neuroprotective agent, would affect HPC theta rhythms in acute HPC slices (in vitro) and anaesthetized rats (in vivo). Whole-cell patch clamp recordings revealed that LTG decreased GABAA-fast transmission in CA3 cells, in vitro. In addition, LTG directly depressed CA3 and CA1 pyramidal neuron excitability. These effects were partially blocked by ZD 7288, a selective HCN blocker, and are consistent with decreased excitability associated with antiepileptic actions. Lamotrigine depressed HPC theta oscillations in vitro, also consistent with its neuronal depressant effects. In contrast, it exerted an opposite, enhancing effect, on theta recorded in vivo. The contradictory in vivo and in vitro results indicate that LTG increases ascending theta activating medial septum/entorhinal synaptic inputs that over-power the depressant effects seen in HPC neurons. These results provide new insights into LTG actions and indicate an opportunity to develop more precise therapeutics for the treatment of dementias, memory disorders and epilepsy.
View details for DOI 10.3390/ijms222413604
View details for PubMedID 34948401
Ketamine Produces a Long-Lasting Enhancement of CA1 Neuron Excitability.
International journal of molecular sciences
2021; 22 (15)
Ketamine is a clinical anesthetic and antidepressant. Although ketamine is a known NMDA receptor antagonist, the mechanisms contributing to antidepression are unclear. This present study examined the loci and duration of ketamine's actions, and the involvement of NMDA receptors. Local field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant and anesthetic concentrations. Effects of NMDA receptor antagonists APV and MK-801, GABA receptor antagonist bicuculline, and a potassium channel blocker TEA were also studied. Ketamine decreased population spike amplitudes during application, but a long-lasting increase in amplitudes was seen during washout. Bicuculline reversed the acute effects of ketamine, but the washout increase was not altered. This long-term increase was statistically significant, sustained for >2 h, and involved postsynaptic mechanisms. A similar effect was produced by MK-801, but was only partially evident with APV, demonstrating the importance of the NMDA receptor ion channel block. TEA also produced a lasting excitability increase, indicating a possible involvement of potassium channel block. This is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anesthesia, while increased excitatory transmission contributes to its antidepressant effects.
View details for DOI 10.3390/ijms22158091
View details for PubMedID 34360854
Molecular diversity of anesthetic actions is evident in electroencephalogram effects in humans and animals
International Journal of Molecular Sciences
2021; 22 (2)
View details for DOI 10.3390/ijms22020495
Offline comparison of brain function monitors for geriatric anaesthetic-induced electroencephalogram changes
British Journal of Anaesthesia
View details for DOI 10.1016/j.bja.2020.12.042
Advances in precision anaesthesia may be found by testing our resistance to change
British Journal of Anaesthesia
View details for DOI 10.1016/j.bja.2020.06.007
A newly developed anesthetic based on a unique chemical core.
Proceedings of the National Academy of Sciences of the United States of America
Intravenous anesthetic agents are associated with cardiovascular instability and poorly tolerated in patients with cardiovascular disease, trauma, or acute systemic illness. We hypothesized that a new class of intravenous (IV) anesthetic molecules that is highly selective for the slow type of gamma-aminobutyric acid type A receptor (GABAAR) could have potent anesthetic efficacy with limited cardiovascular effects. Through in silico screening using our GABAAR model, we identified a class of lead compounds that are N-arylpyrrole derivatives. Electrophysiological analyses using both an in vitro expression system and intact rodent hippocampal brain slice recordings demonstrate a GABAAR-mediated mechanism. In vivo experiments also demonstrate overt anesthetic activity in both tadpoles and rats with a potency slightly greater than that of propofol. Unlike the clinically approved GABAergic anesthetic etomidate, the chemical structure of our N-arylpyrrole derivative is devoid of the chemical moieties producing adrenal suppression. Our class of compounds also shows minimal to no suppression of blood pressure, in marked contrast to the hemodynamic effects of propofol. These compounds are derived from chemical structures not previously associated with anesthesia and demonstrate that selective targeting of GABAAR-slow subtypes may eliminate the hemodynamic side effects associated with conventional IV anesthetics.
View details for DOI 10.1073/pnas.1822076116
View details for PubMedID 31308218
- Wake Up, Neurons! Astrocytes Calling ANESTHESIOLOGY 2019; 130 (3): 361–63
Wake Up, Neurons! Astrocytes Calling.
View details for PubMedID 30707121
Nonlinear dynamics captures brain states at different levels of consciousness in patients anesthetized with propofol.
View details for DOI 10.1371/journal.pone.0223921
Do Complexity Measures of Frontal EEG Distinguish Loss of Consciousness in Geriatric Patients Under Anesthesia?
Frontiers in neuroscience
2018; 12: 645
While geriatric patients have a high likelihood of requiring anesthesia, they carry an increased risk for adverse cognitive outcomes from its use. Previous work suggests this could be mitigated by better intraoperative monitoring using indexes defined by several processed electroencephalogram (EEG) measures. Unfortunately, inconsistencies between patients and anesthetic agents in current analysis techniques have limited the adoption of EEG as standard of care. In attempts to identify new analyses that discriminate clinically-relevant anesthesia timepoints, we tested 1/f frequency scaling as well as measures of complexity from nonlinear dynamics. Specifically, we tested whether analyses that characterize time-delayed embeddings, correlation dimension (CD), phase-space geometric analysis, and multiscale entropy (MSE) capture loss-of-consciousness changes in EEG activity. We performed these analyses on EEG activity collected from a traditionally hard-to-monitor patient population: geriatric patients on beta-adrenergic blockade who were anesthetized using a combination of fentanyl and propofol. We compared these analyses to traditional frequency-derived measures to test how well they discriminated EEG states before and after loss of response to verbal stimuli. We found spectral changes similar to those reported previously during loss of response. We also found significant changes in 1/f frequency scaling. Additionally, we found that our phase-space geometric characterization of time-delayed embeddings showed significant differences before and after loss of response, as did measures of MSE. Our results suggest that our new spectral and complexity measures are capable of capturing subtle differences in EEG activity with anesthesia administration-differences which future work may reveal to improve geriatric patient monitoring.
View details for DOI 10.3389/fnins.2018.00645
View details for PubMedID 30294254
View details for PubMedCentralID PMC6158339
- Can you hear me now? Information processing in primary auditory cortex at loss of consciousness. British journal of anaesthesia 2018; 121 (3): 526-529
Remifentanil and Nitrous Oxide Anesthesia Produces a Unique Pattern of EEG Activity During Loss and Recovery of Response
FRONTIERS IN HUMAN NEUROSCIENCE
2018; 12: 173
Nitrous oxide (N2O) and remifentanil (remi) are used along with other anesthetic and adjuvant agents for routine surgical anesthesia, yet the electroencephalogram (EEG) changes produced by this combination are poorly described. N2O administered alone produces EEG spectral characteristics that are distinct from most hypnotics. Furthermore, EEG frequency-derived trends before and after clinically relevant time points vary depending on N2O concentration. Remifentanil typically increases low frequency and decreases high frequency activity in the EEG, but how it influences N2O's EEG effect is not known. Previous attempts to characterize EEG signals of patients anesthetized with N2O using frequency-derived measures have shown conflicts and inconsistencies. Thus, in addition to determining the spectral characteristics of this unique combination, we also test whether a newly proposed characterization of time-delayed embeddings of the EEG signal tracks loss and recovery of consciousness significantly at clinically relevant time points. We retrospectively investigated the effects of remi and N2O on EEG signals recorded from 32 surgical patients receiving anesthesia for elective abdominal surgeries. Remifentanil and N2O (66%) were co-administered during the procedures. Patients were tested for loss and recovery of response (ROR) to verbal stimuli after induction and upon cessation of anesthesia, respectively. We found that the addition of remifentanil to N2O anesthesia improves the ability of traditional frequency-derived measures, including the Bispectral Index (BIS), to discriminate between loss and ROR. Finally, we found that a novel analysis of EEG using nonlinear dynamics showed more significant differences between states than most spectral measures.
View details for PubMedID 29867405
Can you hear me now? Information processing in primary auditory cortex at loss of consciousness
British Journal of Anaesthesia
2018; 121 (3): 526-529
View details for DOI 10.1016/j.bja.2018.06.008
Do complexity measures of frontal EEG distinguish loss of consciousness in geriatric patients under anesthesia?
Frontiers in Neuroscience
View details for DOI 10.3389/fnins.2018.00645
High Dose Gamma Radiation Selectively Reduces GABAA-slow Inhibition.
2017; 9 (3)
Studies on the effects of gamma radiation on brain tissue have produced markedly differing results, ranging from little effect to major pathology, following irradiation. The present study used control-matched animals to compare effects on a well characterized brain region following gamma irradiation. Male Sprague-Dawley rats were exposed to 60 Gy of whole brain gamma radiation and, after 24-hours, 48-hours, and one-week periods, hippocampal brain slices were isolated and measured for anatomical and physiological differences. There were no major changes observed in tissue appearance or evoked synaptic responses at any post-irradiation time point. However, exposure to 60 Gy of irradiation resulted in a small, but statistically significant (14% change; ANOVA p < 0.005; n = 9) reduction in synaptic inhibition seen at 100 ms, indicating a selective depression of the gamma-aminobutyric acid (GABAA) slow form of inhibition. Population spike (PS) amplitudes also transiently declined by ~ 10% (p < 0.005; n = 9) when comparing the 24-hour group to sham group. Effects on PS amplitude recovered to baseline 48 hour and one week later. There were no obvious negative pathological effects; however, a subtle depression in circuit level inhibition was observed and provides evidence for 'radiomodulation' of brain circuits.
View details for DOI 10.7759/cureus.1076
View details for PubMedID 28401026
Alteration of Interneuron Immunoreactivity and Autophagic Activity in Rat Hippocampus after Single High-Dose Whole-Brain Irradiation.
2017; 9 (6): e1414
The effects of high dose gamma radiation on brain tissue are poorly understood, with both limited and major changes reported. The present study compared the effects of gamma irradiation on the expression of interneuron markers within the hippocampal cornu ammonis 1 (CA1) region with expression in control matched rats. This area was chosen for study because of its well-characterized circuitry. Male Sprague-Dawley rats were exposed to 60 Gy of whole brain gamma radiation and after 24 or 48 hours, the brains were removed, fixed and sectioned to quantitate expression of parvalbumin (PV), calbindin-D28K (CB), reelin, neuropeptide-Y (NPY), and somatostatin. All of these markers increased in expression over the first 48 hours, except NPY, which decreased. This provides novel information on changes in gene expression in the hippocampal interneurons following radiation. Staining for Beclin 1, a marker of autophagy, increased most strongly in the subgranular zone (SGZ) of the dentate gyrus (DG). Overall, the results are consistent with the hypothesis that increased intracellular calcium follows irradiation, leading to an increased expression of calcium binding proteins. Increased autophagy occurs in the neurogenic zone of the dentate hilus, consistent with reduced effective neurogenesis after irradiation.
View details for PubMedID 28861331
View details for PubMedCentralID PMC5576964
Median Raphe Stimulation-Induced Motor Inhibition Concurrent With Suppression of Type 1 and Type 2 Hippocampal Theta
2016; 26 (3): 289-300
This study investigated behavioral, anatomical and electrophysiological effects produced by electrical stimulation of posterior hypothalamic (PH) or median raphe (MR) nuclei, independently and during combined stimulation of both PH and MR. These three stimulation conditions were applied during spontaneous behavior in an open field and during PH stimulation-induced wheel running, while simultaneously recording hippocampal (HPC) field activity. An additional objective was to determine the effects of MR stimulation on Type 1 movement related theta and Type 2 sensory processing related theta. To achieve the latter, when behavioral studies were completed we studied the same rats under urethane anesthesia and then during urethane anesthesia with the addition of atropine sulfate (ATSO4). Here we demonstrated that electrical stimulation of a localized region of the MR nucleus resulted in a profound inhibition of both spontaneously occurring theta related motor behaviors and the theta related motor behaviors induced by electrical stimulation of the PH nucleus. Furthermore, this motor inhibition occurred concurrently with strong suppression of hippocampal theta field oscillations in the freely moving rat, a condition where the theta recorded is Type 2 sensory processing theta occurring coincidently with Type 1 movement related theta (Bland, 1986). Our results indicate that motor inhibition resulted from stimulation of neurons located in the mid central region of the MR, while stimulation in adjacent regions produced variable responses, including movements and theta activity. The present study provided evidence that the pharmacological basis of the suppression of Type 2 sensory processing HPC theta was cholinergic. However, MR inhibition of PH-induced wheel running was not affected by cholinergic blockade, which blocks Type 2 theta, indicating that MR stimulation-induced motor inhibition also requires the suppression of Type 1 theta. © 2015 Wiley Periodicals, Inc.
View details for DOI 10.1002/hipo.22521
View details for Web of Science ID 000373102800003
Mind and Brain: Consciousness in Unresponsive Subjects
2015; 25 (23): R1140-R1142
A new study shows that subjects rendered unresponsive with sedatives do not exhibit a stereotypic 'unconscious' response to direct cortical stimulation; instead, agent-specific effects are seen that can distinguish between unresponsiveness with and without consciousness.
View details for DOI 10.1016/j.cub.2015.10.036
View details for Web of Science ID 000366388600014
View details for PubMedID 26654376
Anesthetic agent-specific effects on synaptic inhibition.
Anesthesia and analgesia
2014; 119 (3): 558-569
Anesthetics enhance γ-aminobutyric acid (GABA)-mediated inhibition in the central nervous system. Different agents have been shown to act on tonic versus synaptic GABA receptors to different degrees, but it remains unknown whether different forms of synaptic inhibition are also differentially engaged. With this in mind, we tested the hypothesis that different types of GABA-mediated synapses exhibit different anesthetic sensitivities. The present study compared effects produced by isoflurane, halothane, pentobarbital, thiopental, and propofol on paired-pulse GABAA receptor-mediated synaptic inhibition. Effects on glutamate-mediated facilitation were also studied.Synaptic responses were measured in rat hippocampal brain slices. Orthodromic paired-pulse stimulation was used to assess anesthetic effects on either glutamate-mediated excitatory inputs or GABA-mediated inhibitory inputs to CA1 neurons. Antidromic stimulation was used to assess anesthetic effects on CA1 background excitability. Agents were studied at equieffective concentrations for population spike depression to compare their relative degree of effect on synaptic inhibition.Differing degrees of anesthetic effect on paired-pulse facilitation at excitatory glutamate synapses were evident, and blocking GABA inhibition revealed a previously unseen presynaptic action for pentobarbital. Although all 5 anesthetics depressed synaptically evoked excitation of CA1 neurons, the involvement of enhanced GABA-mediated inhibition differed considerably among agents. Single-pulse inhibition was enhanced by propofol, thiopental, and pentobarbital, but only marginally by halothane and isoflurane. In contrast, isoflurane enhanced paired-pulse inhibition strongly, as did thiopental, but propofol, pentobarbital, and halothane were less effective.These observations support the idea that different GABA synapses use receptors with differing subunit compositions and that anesthetics exhibit differing degrees of selectivity for these receptors. The differing anesthetic sensitivities seen in the present study, at glutamate and GABA synapses, help explain the unique behavioral/clinical profiles produced by different classes of anesthetics and indicate that there are selective targets for new agent development.
View details for DOI 10.1213/ANE.0000000000000321
View details for PubMedID 24977633
View details for PubMedCentralID PMC4139451
Chaos analysis of EEG during isoflurane-induced loss of righting in rats.
Frontiers in systems neuroscience
2014; 8: 203-?
It has long been known that electroencephalogram (EEG) signals generate chaotic strange attractors and the shape of these attractors correlate with depth of anesthesia. We applied chaos analysis to frontal cortical and hippocampal micro-EEG signals from implanted microelectrodes (layer 4 and CA1, respectively). Rats were taken to and from loss of righting reflex (LORR) with isoflurane and behavioral measures were compared to attractor shape. Resting EEG signals at LORR differed markedly from awake signals, more similar to slow wave sleep signals, and easily discerned in raw recordings (high amplitude slow waves), and in fast Fourier transform analysis (FFT; increased delta power), in good agreement with previous studies. EEG activation stimulated by turning rats on their side, to test righting, produced signals quite similar to awake resting state EEG signals. That is, the high amplitude slow wave activity changed to low amplitude fast activity that lasted for several seconds, before returning to slow wave activity. This occurred regardless of whether the rat was able to right itself, or not. Testing paw pinch and tail clamp responses produced similar EEG activations, even from deep anesthesia when burst suppression dominated the spontaneous EEG. Chaotic attractor shape was far better at discerning between these awake-like signals, at loss of responses, than was FFT analysis. Comparisons are provided between FFT and chaos analysis of EEG during awake walking, slow wave sleep, and isoflurane-induced effects at several depths of anesthesia. Attractors readily discriminated between natural sleep and isoflurane-induced "delta" activity. Chaotic attractor shapes changed gradually through the transition from awake to LORR, indicating that this was not an on/off like transition, but rather a point along a continuum of brain states.
View details for DOI 10.3389/fnsys.2014.00203
View details for PubMedID 25360091
View details for PubMedCentralID PMC4199270
Teaching an Old GABA Receptor New Tricks
ANESTHESIA AND ANALGESIA
2012; 115 (2): 270-273
The accompanying articles in this issue of the journal's special collection describe attempts to improve on the dynamics of distribution and reduce side effects of analogs of etomidate and benzodiazepines. Both classes of drugs have their principal sites of action on γ-aminobutyric acid type A receptors, although at very different binding sites and by different mechanisms of action. Herein, we review the structure of γ-aminobutyric acid type A receptors and describe the location of the 2 likely binding sites. In addition, we describe how these drugs can interact with the nervous system at a systems level. We leave it to other reviewers to discuss whether these new drugs offer true clinical improvements.
View details for DOI 10.1213/ANE.0b013e31824a0b3c
View details for Web of Science ID 000306769500012
View details for PubMedID 22344244
Human Subthalamic Neuron Spiking Exhibits Subtle Responses to Sedatives
2011; 115 (2): 254-264
During deep brain stimulation implant surgery, microelectrode recordings are used to map the location of targeted neurons. The effects produced by propofol or remifentanil on discharge activity of subthalamic neurons were studied intraoperatively to determine whether they alter neuronal activity.Microelectrode recordings from 11 neurons, each from individual patients, were discriminated and analyzed before and after administration of either propofol or remifentanil. Subthalamic neurons in rat brain slices were recorded in patch-clamp to investigate cellular level effects.Neurons discharged at 42 ± 9 spikes/s (mean ± SD) and showed a common pattern of inhibition that lasted 4.3 ms. Unique discharge profiles were evident for each neuron, seen using joint-interval analysis. Propofol (intravenous bolus 0.3 mg/kg) produced sedation, with minor effects on discharge activity (less than 2.0% change in frequency). A prolongation of recurrent inhibition was evident from joint-interval analysis, and propofol's effect peaked within 2 min, with recovery evident at 10 min. Subthalamic neurons recorded in rat brain slices exhibited inhibitory synaptic currents that were prolonged by propofol (155%) but appeared to lack tonic inhibitory currents. Propofol did not alter membrane potential, membrane resistance, current-evoked discharge, or holding current during voltage clamp. Remifentanil (0.05 mg/kg) had little effect on overall subthalamic neuron discharge activity and did not prolong recurrent inhibition.These results help to characterize the circuit properties and feedback inhibition of subthalamic neurons and demonstrate that both propofol and remifentanil produce only minor alterations of subthalamic neuron discharge activity that should not interfere with deep brain stimulation implant surgery.
View details for PubMedID 21701380
- Loss of Recall and the Hippocampal Circuit Effects Produced by Anesthetics 40th Annual Winter Conference on Brain Research HUMANA PRESS INC. 2010: 175–192
Abused Inhalants Enhance GABA-Mediated Synaptic Inhibition
2009; 34 (10): 2296-2304
Abused inhalants are widely used, especially among school-age children and teenagers, and are 'gateway' drugs leading to the abuse of alcohol and other addictive substances. In spite of this widespread use, little is known about the effects produced by inhalants on the central nervous system. The similarity in behavioral effects produced by inhalants and inhaled anesthetics, together with their common chemical features, prompted this study of inhalant actions on a well-characterized anesthetic target, GABA synapses. Whole-cell patch clamp recordings were conducted on CA1 pyramidal neurons in rat hippocampal brain slices to measure effects on resting membrane properties, action potential discharge, and GABA-mediated inhibitory responses. Toluene, 1,1,1-trichloroethane, and trichloroethylene depressed CA1 excitability in a concentration-dependent and reversible manner. This depression appeared to involve enhanced GABA-mediated inhibition, evident in its reversal by a GABA receptor antagonist. Consistent with this, the abused inhalants increased inhibitory postsynaptic potentials produced using minimal stimulation of stratum radiatum inputs to CA1 neurons, in the presence of CNQX and APV to block excitatory synaptic responses and GGP to block GABA(B) responses. The enhanced inhibition appeared to come about by a presynaptic action on GABA nerve terminals, because spontaneous inhibitory postsynaptic current (IPSC) frequency was increased with no change in the amplitude of postsynaptic currents, both in the presence and absence of tetrodotoxin used to block interneuron action potentials and cadmium used to block calcium influx into nerve terminals. The toluene-induced increase in mIPSC frequency was blocked by dantrolene or ryanodine, indicating that the abused inhalant acted to increase the release of calcium from intracellular nerve terminal stores. This presynaptic action produced by abused inhalants is shared by inhaled anesthetics and would contribute to the altered behavioral effects produced by both classes of drugs, and could be especially important in the context of a disruption of learning and memory by abused inhalants.
View details for DOI 10.1038/npp.2009.57
View details for Web of Science ID 000268919100010
View details for PubMedID 19494804
View details for PubMedCentralID PMC2726900
Anesthetics Discriminate Between Tonic and Phasic gamma-Aminobutyric Acid Receptors on Hippocampal CA1 Neurons
ANESTHESIA AND ANALGESIA
2009; 108 (2): 484-490
Anesthesia is produced by a depression of neuronal signaling in the central nervous system (CNS); however, the mechanism(s) of action underlying this depression remain unclear. Recent studies have indicated that anesthetics can enhance inhibition of CNS neurons by increasing current flow through tonic gamma-aminobutyric acid (GABA(A)) receptor gated chloride channels in their membranes. Enhanced tonic inhibition would contribute to CNS depression produced by anesthetics, but it remains to be determined to what extent anesthetic actions at these receptors contribute to CNS depression. In the present study, we compared and contrasted the involvement of tonic versus synaptic GABA(A) receptors in the functional depression of CNS neurons produced by isoflurane and thiopental.In rat hippocampal slices, whole cell patch clamp recordings were used to study anesthetic effects on CA1 neuron intrinsic excitability, and population spike recordings were used to investigate effects on synaptically evoked discharge. These responses were chosen to test whether anesthetic effects on GABA receptors alter single neuron discharge and/or circuit level synaptic functioning. Phasic (synaptic) GABA receptors were selectively blocked using the GABA(A) antagonist gabazine and tonic responses were blocked using the chloride channel blocker picrotoxin.Clinically relevant and equi-effective concentrations of thiopental and isoflurane depressed CA1 neuron synaptically evoked discharge. This depression was partially reversed by blocking synaptic GABA(A) receptors with gabazine (20 microM). The thiopental-induced depression was reversed by approximately 60%, but the isoflurane-induced depression was reversed by only approximately 20%. Blocking tonic GABA(A) receptors with the addition of 100 microM picrotoxin produced an additional 40% reversal of the thiopental-induced depression, but no additional reversal was seen for isoflurane-depressed responses. In response to direct DC current injection, CA1 neuron discharge was depressed by thiopental and membrane conductance was increased. Both of these effects were reversed by picrotoxin, but not by gabazine. Isoflurane, in contrast, neither depressed current-evoked discharge, nor altered the membrane conductance of CA1 neurons.These results indicate that general anesthetics discriminate between synaptic and tonic GABA(A) receptors. Effects on both phasic and tonic receptors combined to depress circuit responses produced by thiopental, whereas only effects on synaptic GABA receptors appeared to play an important role for isoflurane. Together with the other known sites of action for these two anesthetics, our results support a multisite, agent-specific mechanism for anesthetic actions.
View details for DOI 10.1213/ane.0b013e3181904571
View details for Web of Science ID 000262590000016
View details for PubMedID 19151276
View details for PubMedCentralID PMC2630469
Slow GABA(A) mediated synaptic transmission in rat visual cortex
Previous reports of inhibition in the neocortex suggest that inhibition is mediated predominantly through GABA(A) receptors exhibiting fast kinetics. Within the hippocampus, it has been shown that GABA(A) responses can take the form of either fast or slow response kinetics. Our findings indicate, for the first time, that the neocortex displays synaptic responses with slow GABA(A) receptor mediated inhibitory postsynaptic currents (IPSCs). These IPSCs are kinetically and pharmacologically similar to responses found in the hippocampus, although the anatomical specificity of evoked responses is unique from hippocampus. Spontaneous slow GABA(A) IPSCs were recorded from both pyramidal and inhibitory neurons in rat visual cortex.GABA(A) slow IPSCs were significantly different from fast responses with respect to rise times and decay time constants, but not amplitudes. Spontaneously occurring GABA(A) slow IPSCs were nearly 100 times less frequent than fast sIPSCs and both were completely abolished by the chloride channel blocker, picrotoxin. The GABA(A) subunit-specific antagonist, furosemide, depressed spontaneous and evoked GABA(A) fast IPSCs, but not slow GABA(A)-mediated IPSCs. Anatomical specificity was evident using minimal stimulation: IPSCs with slow kinetics were evoked predominantly through stimulation of layer 1/2 apical dendritic zones of layer 4 pyramidal neurons and across their basal dendrites, while GABA(A) fast IPSCs were evoked through stimulation throughout the dendritic arborization. Many evoked IPSCs were also composed of a combination of fast and slow IPSC components.GABA(A) slow IPSCs displayed durations that were approximately 4 fold longer than typical GABA(A)fast IPSCs, but shorter than GABA(B)-mediated inhibition. The anatomical and pharmacological specificity of evoked slow IPSCs suggests a unique origin of synaptic input. Incorporating GABA(A) slow IPSCs into computational models of cortical function will help improve our understanding of cortical information processing.
View details for DOI 10.1186/1471-2202-9-8
View details for Web of Science ID 000253536800002
View details for PubMedID 18199338
View details for PubMedCentralID PMC2245967
Cellular actions of urethane on rat visual cortical neurons in vitro
JOURNAL OF NEUROPHYSIOLOGY
2006; 95 (6): 3865-3874
Urethane is widely used in neurophysiological experiments to anesthetize animals, yet little is known about its actions at the cellular and synaptic levels. This limits our ability to model systems-level cortical function using results from urethane-anesthetized preparations. The present study found that action potential discharge of cortical neurons in vitro, in response to depolarizing current, was strongly depressed by urethane and this was accompanied by a significant decrease in membrane resistance. Voltage-clamp experiments suggest that the mechanism of this depression involves selective activation of a Ba2+-sensitive K+ leak conductance. Urethane did not alter excitatory glutamate-mediated or inhibitory (GABA(A)- or GABA(B)-mediated) synaptic transmission. Neither the amplitude nor decay time constant of GABA(A)- or GABA(B)-mediated monosynaptic inhibitory postsynaptic currents (IPSCs) were altered by urethane, nor was the frequency of spontaneous IPSCs. These results are consistent with observations seen in vivo during urethane anesthesia where urethane produced minimal disruption of signal transmission in the neocortex.
View details for DOI 10.1152/jn.01196.2005
View details for Web of Science ID 000237653900050
View details for PubMedID 16510775
- Anesthesia in silico ANESTHESIOLOGY 2006; 104 (3): 400-402
Isoflurane depresses hippocampal CA1 glutamate nerve terminals without inhibiting fiber volleys
Anesthetic-induced CNS depression is thought to involve reduction of glutamate release from nerve terminals. Recent studies suggest that isoflurane reduces glutamate release by block of Na channels. To further investigate this question we examined the actions of isoflurane, TTX, extracellular Ca2+, CNQX and stimulus voltage (stim) on glutamate-mediated transmission at hippocampal excitatory synapses. EPSPs were recorded from CA1 neurons in rat hippocampal brain slices in response to Schaffer-collateral fiber stimulation.Isoflurane (350 microM; 1 MAC) reversibly depressed EPSP amplitudes by ~60% while facilitation increased approximately 20%. Consistent with previous studies, these results indicate a presynaptic site of action that involves reduced excitation-release coupling. EPSPs were depressed to comparable levels by TTX (60 nM) or lowered stim, but facilitation was not changed, indicating a simple failure of axonal conduction. Similarly, partial antagonism of postsynaptic glutamate receptors with CNQX (10 microM) depressed EPSP amplitudes with no change in facilitation. However, EPSP depression by low external Ca2+ (0.8 mM) was accompanied by an increase in facilitation comparable to isoflurane. Isoflurane depression of EPSP amplitudes could also be partly reversed by high external Ca2+ (4 mM) that also decreased facilitation. Isoflurane or low Ca2+ markedly reduced the slopes of fiber volley (FV)-EPSP input-output curves, consistent with little or no effect on FVs. By contrast, TTX didn't alter the FV-EPSP curve slope, indicating that EPSP depression resulted from FV depression. FVs were remarkably resistant to isoflurane. Somatic spike currents were unaffected by 350 microM (1 MAC) isoflurane as well. The EC50 for isoflurane depression of FVs was approximately 2.8 mM (12 vol. %; 8 MAC).Isoflurane appears to depress CA1 synapses at presynaptic sites downstream from Na channels, as evident by the increased facilitation that accompanies EPSP depression. Fiber volleys did not exhibit depression by isoflurane, as has been reported for other brain regions.
View details for DOI 10.1186/1471-2202-7-5
View details for Web of Science ID 000235339000001
View details for PubMedID 16409641
View details for PubMedCentralID PMC1369004
Anesthetic-induced burst suppression EEG activity requires glutamate-mediated excitatory synaptic transmission
2005; 15 (9): 1322-1331
Many anesthetics evoke electroencephalogram (EEG) burst suppression activity in humans and animals during anesthesia, and the mechanisms underlying this activity remain unclear. The present study used a rat neocortical brain slice EEG preparation to investigate excitatory synaptic mechanisms underlying anesthetic-induced burst suppression activity. Excitatory synaptic mechanisms associated with burst suppression activity were probed using glutamate receptor antagonists (CNQX and APV), GABA receptor antagonists, and simultaneous whole cell patch clamp and microelectrode EEG recordings. Clinically relevant concentrations of thiopental (50--70 microM), propofol (5--10 microM) or isoflurane (0.7--2.1 vol%, 0.5--1.5 rat minimum aveolar concentration (MAC), 200--700 microM) evoked delta slow wave activity and burst suppression EEG patterns similar to in vivo responses. These effects on EEG signals were blocked by glutamate receptor antagonists CNQX (8.6 microM) or APV (50 microM). Depolarizing intracellular bursts (amplitude=34.7+/-4.5 mV; half width=132+/-60 ms) always accompanied EEG bursts, and hyperpolarization increased intracellular burst amplitudes. Barrages of glutamate-mediated excitatory events initiated EEG bursting activity. Glutamate-mediated excitatory postsynaptic currents were significantly depressed by higher anesthetic concentrations that depressed burst suppression EEG activity. A GABA(A) agonist produced a similar EEG effect to the anesthetics. It appears that anesthetic effects at both glutamate and GABA synapses contribute to EEG patterns seen during anesthesia.
View details for DOI 10.1093/cercor/bhi015
View details for Web of Science ID 000231296900005
View details for PubMedID 15647528
Multiple synaptic and membrane sites of anesthetic action in the CA1 region of rat hippocampal slices
Anesthesia is produced by a depression of central nervous system function, however, the sites and mechanisms of action underlying this depression remain poorly defined. The present study compared and contrasted effects produced by five general anesthetics on synaptic circuitry in the CA1 region of hippocampal slices.At clinically relevant and equi-effective concentrations, presynaptic and postsynaptic anesthetic actions were evident at glutamate-mediated excitatory synapses and at GABA-mediated inhibitory synapses. In addition, depressant effects on membrane excitability were observed for CA1 neuron discharge in response to direct current depolarization. Combined actions at several of these sites contributed to CA1 circuit depression, but the relative degree of effect at each site was different for each anesthetic studied. For example, most of propofol's depressant effect (> 70 %) was reversed with a GABA antagonist, but only a minor portion of isoflurane's depression was reversed (< 20 %). Differences were also apparent on glutamate synapses-pentobarbital depressed transmission by > 50 %, but thiopental by only < 25 %.These results, in as much as they may be relevant to anesthesia, indicate that general anesthetics act at several discrete sites, supporting a multi-site, agent specific theory for anesthetic actions. No single effect site (e.g. GABA synapses) or mechanism of action (e.g. depressed membrane excitability) could account for all of the effects produced for any anesthetic studied.
View details for DOI 10.1186/1471-2202-5-52
View details for Web of Science ID 000226606200004
View details for PubMedID 15579203
View details for PubMedCentralID PMC543467
Determination of diffusion and partition coefficients of propofol in rat brain tissue: implications for studies of drug action in vitro
BRITISH JOURNAL OF ANAESTHESIA
2004; 93 (6): 810-817
Propofol (2,6-diisopropylphenol) is a widely used general anaesthetic that modulates gamma-aminobutyric acid type A (GABA(A)) receptors, the major inhibitory neurotransmitter receptor in the brain. Previous studies have found that the concentration of propofol that is required to affect synaptic inhibition in brain slices is much higher than the free concentration that is achieved clinically and that modulates isolated receptors. We tested whether this is accounted for by slow equilibration in brain tissue, and determined the concentration that must be applied to achieve appropriate brain levels.Rat brain slices 300-microm thick were placed in a solution of 100 microM propofol in artificial cerebrospinal fluid for times ranging from 7.5 to 480 min. Concentrations in these slices were measured by HPLC to determine diffusion and partition coefficients. Electrophysiological measurements of the rate at which effects of 5 microM propofol developed were compared with the calculated rate of increase in tissue concentration.The diffusion coefficient was approximately 0.02x10(-6) cm2 s(-1), and the brain:artificial cerebrospinal fluid partition coefficient was 36. Diffusion times in brain slices agreed well with time course measurements of propofol-induced depression of synaptic responses, which continued to increase over 5 h. This depression was reversed by blocking GABA inhibition with picrotoxin (100 microM).Propofol does enhance inhibition in brain slices at a concentration of 0.63 microM in the superfusate, which produces brain concentrations corresponding with those achieved in vivo, but equilibration requires several hours. It is likely that slow diffusion to GABA receptors accounts for the high concentrations (>10 microM) that were needed to depress evoked responses in previous investigations.
View details for DOI 10.1093/bja/aeh272
View details for Web of Science ID 000225250500012
View details for PubMedID 15377586
Major role for tonic GABA(A) conductances in anesthetic suppression of intrinsic neuronal excitability
JOURNAL OF NEUROPHYSIOLOGY
2004; 92 (3): 1658-1667
Anesthetics appear to produce neurodepression by altering synaptic transmission and/or intrinsic neuronal excitability. Propofol, a widely used anesthetic, has proposed effects on many targets, ranging from sodium channels to GABA(A) inhibition. We examined effects of propofol on the intrinsic excitability of hippocampal CA1 neurons (primarily interneurons) recorded from adult rat brain slices. Propofol strongly depressed action potential production induced by DC injection, synaptic stimulation, or high-potassium solutions. Propofol-induced depression of intrinsic excitability was completely reversed by bicuculline and picrotoxin but was strychnine-insensitive, implicating GABA(A) but not glycine receptors. Propofol strongly enhanced inhibitory postsynaptic currents (IPSCs) and induced a tonic GABA(A)-mediated current. We pharmacologically differentiated tonic and phasic (synaptic) GABA(A)-mediated inhibition using the GABA(A) receptor antagonist SR95531 (gabazine). Gabazine (20 microM) completely blocked both evoked and spontaneous IPSCs but failed to block the propofol-induced depression of intrinsic excitability, implicating tonic, but not phasic, GABA(A) inhibition. Glutamatergic synaptic responses were not altered by propofol (< or =30 microM). Similar results were found in both interneurons and pyramidal cells and with the chemically unrelated anesthetic thiopental. These results suggest that suppression of CA1 neuron intrinsic excitability, by these anesthetics, is largely due to activation of tonic GABA(A) conductances; although other sites of action may play important roles in affecting synaptic transmission, which also can produce strong neurodepression. We propose that for some anesthetics, suppression of intrinsic excitability, mediated by tonic GABA(A) conductances, operates in conjunction with effects on synaptic transmission, mediated by other mechanisms, to depress hippocampal function during anesthesia.
View details for DOI 10.1152/jn.00223.2004
View details for Web of Science ID 000223539400037
View details for PubMedID 15140905
Anesthetic properties of 4-iodopropofol - Implications for mechanisms of anesthesia
2001; 94 (6): 1050-1057
Positive modulation of gamma-aminobutyric acid type A (GABAA) receptor function is recognized as an important component of the central nervous system depressant effects of many general anesthetics, including propofol. The role for GABAA receptors as an essential site in the anesthetic actions of propofol was recently challenged by a report that the propofol analog 4-iodopropofol (4-iodo-2,6-diisopropylphenol) potentiated and directly activated GABAA receptors, yet was devoid of sedative-anesthetic effects in rats after intraperitoneal injection. Given the important implications of these findings for theories of anesthesia, the authors compared the effects of 4-iodopropofol with those of propofol using established in vivo and in vitro assays of both GABAA receptor-dependent and -independent anesthetic actions.The effects of propofol and 4-iodopropofol were analyzed on heterologously expressed recombinant human GABAA alpha1beta2gamma2 receptors, evoked population spike amplitudes in rat hippocampal slices, and glutamate release from rat cerebrocortical synaptosomes in vitro. Anesthetic potency was determined by loss of righting reflex in Xenopus laevis tadpoles, in mice after intraperitoneal injection, and in rats after intravenous injection.Like propofol, 4-iodopropofol enhanced GABA-induced currents in recombinant GABAA receptors, inhibited synaptic transmission in rat hippocampal slices, and inhibited sodium channel-mediated glutamate release from synaptosomes, but with reduced potency. After intraperitoneal injection, 4-iodopropofol did not produce anesthesia in mice, but it was not detected in serum or brain. However, 4-iodopropofol did produce anesthesia in tadpoles (EC50 = 2.5 +/- 0.5 microM) and in rats after intravenous injection (ED50 = 49 +/- 6.2 mg/kg).Propofol and 4-iodopropofol produced similar actions on several previously identified cellular and molecular targets of general anesthetic action, and both compounds induced anesthesia in tadpoles and rats. The failure of 4-iodopropofol to induce anesthesia in rodents after intraperitoneal injection is attributed to a pharmacokinetic difference from propofol rather than to major pharmacodynamic differences.
View details for Web of Science ID 000169137700016
View details for PubMedID 11465597
Agent-selective effects of volatile anesthetics on GABA(A) receptor-mediated synaptic inhibition in hippocampal interneurons
2001; 94 (2): 340-347
A relatively small number of inhibitory interneurons can control the excitability and synchronization of large numbers of pyramidal cells in hippocampus and other cortical regions. Thus, anesthetic modulation of interneurons could play an important role for the maintenance of anesthesia. The aim of this study was to compare effects produced by volatile anesthetics on inhibitory postsynaptic currents (IPSCs) of rat hippocampal interneurons.Pharmacologically isolated gamma-aminobutyric acid type A (GABAA) receptor-mediated IPSCs were recorded with whole cell patch-clamp techniques in visually identified interneurons of rat hippocampal slices. Neurons located in the stratum radiatum-lacunosum moleculare of the CA1 region were studied. The effects of clinically relevant concentrations (1.0 rat minimum alveolar concentration) of halothane, enflurane, isoflurane, and sevoflurane were compared on kinetics of both stimulus-evoked and spontaneous GABAA receptor-mediated IPSCs in interneurons.Halothane (1.2 vol% approximately 0.35 mm), enflurane (2.2 vol% approximately 0.60 mm), isoflurane (1.4 vol% approximately 0.50 mm), and sevoflurane (2.7 vol% approximately 0.40 mm) preferentially depressed evoked IPSC amplitudes to 79.8 +/- 9.3% of control (n = 5), 38.2 +/- 8.6% (n = 6), 52.4 +/- 8.4% (n = 5), and 46.1 +/- 16.0% (n = 8), respectively. In addition, all anesthetics differentially prolonged the decay time constant of evoked IPSCs to 290.1 +/- 33.2% of control, 423.6 +/- 47.1, 277.0 +/- 32.2, and 529 +/- 48.5%, respectively. The frequencies of spontaneous IPSCs were increased by all anesthetics (twofold to threefold). Thus, the total negative charge transfer mediated by GABAA receptors between synaptically connected interneurons was enhanced by all anesthetics.Volatile anesthetics differentially enhanced GABAA receptor-mediated synaptic inhibition in rat hippocampal interneurons, suggesting that hippocampal interneuron circuits are depressed by these anesthetics in an agent-specific manner.
View details for Web of Science ID 000166694900021
View details for PubMedID 11176100
Membrane and synaptic actions of halothane on rat hippocampal pyramidal neurons and inhibitory interneurons
JOURNAL OF NEUROSCIENCE
2000; 20 (16): 5915-5923
A relatively small number of inhibitory interneurons can control the excitability and synchronization of large numbers of pyramidal neurons in hippocampus and other cortical regions. Thus, anesthetic modulation of interneurons could play an important role during anesthesia. The aim of this study was to investigate effects of a general anesthetic, halothane, on membrane and synaptic properties of rat hippocampal interneurons. GABA receptor-mediated IPSCs were recorded with whole-cell patch-clamp techniques in visually identified CA1 pyramidal cells and interneurons located at the border of stratum lacunosum-moleculare and stratum radiatum. Halothane (0.35 mm congruent with 1.2 vol%) depressed evoked IPSC amplitudes recorded from both pyramidal cells and inhibitory interneurons. Also, halothane considerably prolonged the decay time constant of evoked IPSCs in pyramidal cells and interneurons. The frequencies of miniature IPSCs were increased by halothane (two- to threefold) in both types of neuron. On the other hand, halothane effects on resting membrane potentials were variable but minimal in both types of neurons. In current-clamp recordings, halothane depressed EPSP amplitudes and increased IPSP amplitudes recorded from both types of neurons. In addition, halothane increased the failure rate of synaptically evoked action potentials. Taken together, these data provide evidence that halothane increases GABA(A) receptor-mediated synaptic inhibition between synaptically connected interneurons and depresses excitatory transmission, similar to effects observed in pyramidal neurons.
View details for Web of Science ID 000088676400005
View details for PubMedID 10934238
- Ischemia-induced eeg waveform alterations recorded from cortical brain slices LIPPINCOTT-RAVEN PUBL. 1997: A688
- Halothane enhances presynaptic GABA release by increasing internal calcium LIPPINCOTT-RAVEN PUBL. 1997: A626
Volatile anesthetics depress glutamate transmission via presynaptic actions
American-Society-of-Anesthesiologists Annual Meeting
LIPPINCOTT WILLIAMS & WILKINS. 1996: 823–34
Recent evidence for a presynaptic depression of glutamate release produced by volatile anesthetics prompted the current study of isoflurane and halothane effects on glutamate-mediated transmission in the mammalian central nervous system.Electrophysiologic recordings from CA1 neurons in rat hippocampal brain slices were used to measure anesthetic effects on glutamate-mediated excitatory postsynaptic potential (EPSP) amplitudes and paired pulse facilitation. Paired pulse facilitation is known to be altered when the calcium-dependent release of glutamate is depressed, but not when EPSP amplitudes are depressed by postsynaptic mechanisms.Isoflurane depressed EPSP amplitudes over a concentration range of 0.35-2.8 vol %, with a 50% depression (EC50) occurring at 1.0 vol % (0.71 rat minimum alveolar concentration). This depression was accompanied by an increase in paired-pulse facilitation of approximately 30% at 1.7 vol %, using interpulse intervals of 120 ms. Halothane depressed EPSP amplitudes in a concentration-dependent manner (0.3-2.4 vol %, EC50 = 1.1 minimum alveolar concentration; 1.3 vol %) and also increased facilitation by approximately 20% at 1.2 vol %. These effects persisted in the presence of 10 microM bicuculline, indicating that enhanced gamma-aminobutyric acid-mediated inhibition was not involved. The anesthetic-induced increase in facilitation and EPSP depression was mimicked by lowering extracellular calcium, which is known to depress glutamate release at these synapses. The postsynaptic glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione depressed EPSP amplitudes with no change in facilitation.Our results confirm earlier findings that clinically relevant concentrations of volatile anesthetics depress glutamate-mediated synaptic transmission. The observed increases in synaptic facilitation support recent findings from biochemical and electrophysiologic studies indicating presynaptic sites of action contribute to anesthetic-induced depression of excitatory transmission. This anesthetic-induced reduction in glutamate release would contribute to the central nervous system depression associated with anesthesia by adding to postsynaptic depressant actions on glutamate receptors.
View details for Web of Science ID A1996VM09800020
View details for PubMedID 8873553
Volatile anesthetics enhance presynaptic GABA release
LIPPINCOTT-RAVEN PUBL. 1996: A706
View details for Web of Science ID A1996VM46600706
Calcium electrode measures aqueous volatile anesthetic concentrations
LIPPINCOTT-RAVEN PUBL. 1996: A684
View details for Web of Science ID A1996VM46600684
Halothane prolongs GABA(A) fast and slow inhibitory currents
LIPPINCOTT-RAVEN PUBL. 1996: A673
View details for Web of Science ID A1996VM46600673
Halothane enhances feedback but feedforward GABA inhibition
LIPPINCOTT-RAVEN PUBL. 1996: A674
View details for Web of Science ID A1996VM46600674
RILUZOLE PRODUCES A POTENT, USE-DEPENDENT DEPRESSION OF SYNAPTIC TRANSMISSION IN RAT HIPPOCAMPAL CA-1 NEURONS
LIPPINCOTT-RAVEN PUBL. 1995: A745
View details for Web of Science ID A1995RX68500745
PROPOFOL ENHANCES GABA(A,SLOW) FEEDFORWARD INHIBITION IN CA-1 NEURON DENDRITES
LIPPINCOTT-RAVEN PUBL. 1995: A751
View details for Web of Science ID A1995RX68500751
PROPOFOL, THIOPENTAL AND ISOFLURANE-INDUCED BURST SUPPRESSION EEG PATTERNS ARE INTRINSIC TO NEOCORTEX
LIPPINCOTT-RAVEN PUBL. 1995: A750
View details for Web of Science ID A1995RX68500750
PROLONGED GABA-A CHLORIDE CURRENTS UNDERLIE THE THIOPENTAL INDUCED SLOWING OF EEG FREQUENCIES
LIPPINCOTT-RAVEN PUBL. 1994: A798
View details for Web of Science ID A1994PJ09100797
GABA-A INHIBITION CONTRIBUTES MORE TO THE ANESTHETIC ACTIONS OF THIOPENTAL THAN HALOTHANE
LIPPINCOTT-RAVEN PUBL. 1994: A801
View details for Web of Science ID A1994PJ09100800
STRUCTURAL AND FUNCTIONAL SPECIALIZATION OF A-DELTA-FIBER AND C-FIBER FREE NERVE-ENDINGS INNERVATING RABBIT CORNEAL EPITHELIUM
JOURNAL OF NEUROSCIENCE
1993; 13 (10): 4511-4524
An in vitro preparation of rabbit cornea was used to compare anatomical specialization and electrophysiological responses of A delta and C fiber sensory afferents which terminate as free nerve endings. Living nerve endings were visualized using epifluorescence microscopy and the vital dye 4-di2-ASP, and response properties were determined using microstimulation and recording of fiber discharge activity. Fiber type was determined based on conduction velocity measurement and preferred stimulus energy (modality) of each fiber. Four modality-specific fiber populations were identified: (1) slowly adapting C fiber cold receptors (conduction velocity of 0.25-1.6 m/sec), (2) C fiber chemosensitive units with mixed phasic and tonic activity (1.1-1.8 m/sec), (3) rapidly adapting mechanosensitive A delta fibers (1.5-2.8 m/sec), and (4) high-threshold mechano/heat (> 350 dyne or > 40 degrees C) phasic A delta afferents (3.5-4.4 m/sec). In addition to these physiological differences, anatomical specialization was also noted. A delta fiber nerve endings were distinguished from those of C fibers by thin, elongated sensory endings that ran parallel to the corneal surface; C fiber endings formed short, branching clusters that ran mostly perpendicular to the surface. The elongated structure of A delta nerve endings was associated with directional selectivity for mechanical stimuli. These results substantiate previous suggestions that free nerve endings can exhibit both structural and functional specialization.
View details for Web of Science ID A1993MB16400033
View details for PubMedID 8410200
TONIC CORNEAL NERVE INJURY DISCHARGE CAN BE REDUCED BY LIDOCAINE WITHOUT ALTERING NERVE-CONDUCTION
LIPPINCOTT-RAVEN PUBL. 1991: 1076
View details for Web of Science ID A1991FC76202005
ANESTHETIC ACTIONS IN THE HIPPOCAMPAL-FORMATION
CONF ON MOLECULAR AND CELLULAR MECHANISMS OF ALCOHOL AND ANESTHETICS
NEW YORK ACAD SCIENCES. 1991: 37–53
View details for Web of Science ID A1991BT99V00004
2 MECHANISMS FOR ANESTHETIC-INDUCED ENHANCEMENT OF GABA-A-MEDIATED NEURONAL INHIBITION
CONF ON MOLECULAR AND CELLULAR MECHANISMS OF ALCOHOL AND ANESTHETICS
NEW YORK ACAD SCIENCES. 1991: 91–97
View details for Web of Science ID A1991BT99V00008
INHALATION ANESTHETICS EXHIBIT PATHWAY-SPECIFIC AND DIFFERENTIAL ACTIONS ON HIPPOCAMPAL SYNAPTIC RESPONSES INVITRO
BRITISH JOURNAL OF ANAESTHESIA
1988; 60 (6): 680-691
The effects of halothane, isoflurane and enflurane were compared on three CNS excitatory synaptic pathways in vitro, to determine whether selective actions described in vivo result from differential effects on anatomically distinct cortical pathways and neurone populations. Halothane (0.25-1.25 vol%) depressed postsynaptic excitability of CA1 pyramidal neurones in response to activation of stratum radiatum synaptic inputs, and concentration-dependent excitatory (0.25-1.25 vol%) and depressant (1.5-2.0 vol%) actions were observed on dentate granule neurone excitability and perforant path evoked synaptic responses. In contrast, isoflurane increased CA1 neurone excitability (0.25-0.75 vol%) and produced postsynaptic depression of dentate neurones (0.5-4.0 vol%). Enflurane also increased CA1 excitability (0.5-4.0 vol%), but depressed synaptic responses at equivalent concentrations, and produced mixed excitatory (0.25-1.0 vol%) and depressant (1.0-4.0 vol%) effects on dentate synaptic responses. Differential actions were also observed for the three anaesthetics on stratum oriens excitatory inputs to CA1 neurones, and on antidromic responses. A good correlation (r = 0.992) exists between the membrane/buffer partition coefficients of these anaesthetics and their half-maximal concentrations for depression of synaptic responses; however, this correlation does not reflect the different, anaesthetic-specific actions observed. The results indicate that inhalation anaesthetics act at multiple and selective hydrophobic recognition sites which are heterogenously distributed on different synaptic pathways.
View details for Web of Science ID A1988N301300015
View details for PubMedID 2837263
CHOLINERGIC THETA RHYTHM IN TRANSECTED HIPPOCAMPAL SLICES - INDEPENDENT CA1 AND DENTATE GENERATORS
1987; 436 (2): 217-222
The controversy concerning intrahippocampal theta (theta) generators, arising as a result of in vivo investigations, prompted us to record theta-activity from isolated populations of CA1 pyramidal or dentate granule neurons in vitro. In the present study, transected slices (trans-slices) of the hippocampal formation were used to isolate the CA1 area from the dentate gyrus, providing a method for testing the 'two generator' hypothesis. We demonstrated that neurons in both the CA1 area and dentate gyrus could independently generate carbachol-induced (type 2) electroencephalogram (EEG) theta-activity. This activity could be completely blocked by the muscarinic receptor antagonist atropine sulfate but was unaffected by the nicotinic blocker, (+)-tubocurarine. These in vitro results provide the first direct evidence for the two-generator hypothesis and confirm the cholinergic-muscarinic nature of type 2 slow wave theta.
View details for Web of Science ID A1987L659500002
View details for PubMedID 3435823
ANESTHETICS PRODUCE DIFFERENTIAL ACTIONS ON MEMBRANE RESPONSES OF THE CRAYFISH STRETCH-RECEPTOR NEURON
EUROPEAN JOURNAL OF PHARMACOLOGY
1987; 141 (1): 67-77
The actions of ethanol, halothane and pentobarbital on the membrane electrical properties and synaptic transmission of isolated crayfish stretch receptor neurons were studied to determine possible sites of action contributing to differential effects previously described on physiological discharge activity. The three agents depressed GABA-mediated transmission and altered postsynaptic membrane electrical properties. Both pre- and postsynaptic sites of action appeared to contribute to the anesthetic-induced alteration of neuronal function. The agents studied produced different, concentration-dependent, membrane effects which included biphasic actions on membrane resistance and spike threshold. The results suggest that multiple-sites of action are involved and different anesthetics may not act via the same mechanism(s) at these sites.
View details for Web of Science ID A1987J947800008
View details for PubMedID 3666028
ANESTHETICS PRODUCE DIFFERENTIAL ACTIONS ON THE DISCHARGE ACTIVITY OF A SINGLE NEURON
EUROPEAN JOURNAL OF PHARMACOLOGY
1987; 139 (1): 43-52
The effects of 26 anesthetic agents were studied on the rhythmical discharge activity of a single isolated neuron (crayfish stretch receptor). Many of these agents produced concentration-dependent biphasic responses (excitation and depression), and some also induced altered discharge patterns (burst activity). The dominant effect of a few of the anesthetics was excitation (e.g. alphaxolone); depression (e.g. decanol); or burst activity (e.g. benzocaine). A correlation was found to exist between equieffective concentrations in the perfusate and membrane/buffer partition coefficients; however, this general phenomenon does not provide an explanation for the biphasic or differential responses. These results demonstrate that selective interactions occur at the level of the single neuron, and suggest the existence of recognition sites in neuronal membranes which can discriminate structural differences of anesthetics.
View details for Web of Science ID A1987J329000005
View details for PubMedID 3653240
CARBACHOL-INDUCED EEG THETA-ACTIVITY IN HIPPOCAMPAL BRAIN-SLICES
1987; 405 (1): 196-198
Application of the cholinergic agonist carbachol (50 microM) produced theta-like rhythmical waveforms, recorded in the stratum moleculare of the dentate gyrus. Atropine sulfate (50 microM) antagonized the carbachol-induced theta-like activity, consistent with this action of atropine in vivo. These results provide the first direct evidence that hippocampal neurons are capable of producing synchronized slow-wave activity when isolated from pulsed rhythmic inputs of the medial septum and other brain regions.
View details for Web of Science ID A1987G499900026
View details for PubMedID 3567594
ENFLURANE-INDUCED BURST FIRING OF HIPPOCAMPAL CA 1 NEURONS - INVITRO STUDIES USING A BRAIN SLICE PREPARATION
BRITISH JOURNAL OF ANAESTHESIA
1987; 59 (3): 369-378
Enflurane can produce seizure activity in the cortical EEG, in vivo, at concentrations associated with surgical anaesthesia. The present study was designed to determine whether this seizure-like burst activity could occur in isolated cortical neurones. Enflurane altered synaptic transmission in the in vitro rat hippocampal slice preparation and produced seizure-like burst discharges of CA 1 neurones, at vapour concentrations equivalent to those obtained during anaesthesia (2-6 vol%; 0.5-1.5 mmol litre-1). Burst discharges occurred both spontaneously and in response to stimulation of stratum radiatum fibres in the CA 1 pyramidal region, but not in the dentate area. Low concentrations of enflurane (approx. 0.75 mmol litre-1), decreased the field potential responses of CA 1 neurones; however, dentate granule neurone responses were increased. Input/output analyses of field excitatory post-synaptic potential (EPSP) and population spike amplitudes revealed that the enflurane-induced depression of field potential responses was associated with decreases in synaptic input, whereas burst activity resulted from a decrease in the threshold of CA 1 neurones.
View details for Web of Science ID A1987G223300019
View details for PubMedID 3828186
BARBITURATE EFFECTS ON HIPPOCAMPAL EXCITATORY SYNAPTIC RESPONSES ARE SELECTIVE AND PATHWAY SPECIFIC
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
1987; 65 (3): 385-394
Barbiturate actions on excitatory synaptic responses in CA 1 and dentate regions of hippocampal slices were studied to determine whether different effects occur on anatomically distinct synaptic pathways. Pentobarbital facilitated transmission between stratum radiatum inputs and CA 1 neurons at low concentrations (0.02-0.08 mM) and produced postsynaptic depression at higher concentrations. Only depression was observed for stratum oriens inputs to CA 1 and perforant path inputs to dentate granulae neurons. The (+) isomer of pentobarbital was approximately four times more potent than the (-) isomer of racemic mixture. Phenobarbital (0.04-0.12 mM) produced only depression of synaptic responses in CA 1 and dentate pathways. Comparison of effect on field excitatory postsynaptic potentials and population spike responses indicated that the barbiturates act at selective and pathway-specific sites. The results provide further evidence for specific cellular and membrane recognition sites for barbiturate action.
View details for Web of Science ID A1987G610700017
View details for PubMedID 3034390
THETA IN HIPPOCAMPAL SLICES - RELATION TO SYNAPTIC RESPONSES OF DENTATE NEURONS
BRAIN RESEARCH BULLETIN
1987; 18 (1): 25-27
The effects of cholinergic agents on isolated dentate neurons were studied to characterize cellular mechanisms underlying carbachol-induced 'theta' EEG activity. Carbachol, eserine, and acetylcholine produced a synchronization of slow wave activity (theta) accompanied by depression of perforant path to dentate field potentials. These effects were antagonized by atropine but not d-tubocurarine. The results suggest that muscarinic receptors mediate theta activity resulting from a depolarization of dentate neurons.
View details for Web of Science ID A1987F955800005
View details for PubMedID 3030510
Carbachol induced rhythmical slow wave activity recorded from dentate granule neurons in vitro.
Proceedings of the Western Pharmacology Society
1986; 29: 159-161
View details for PubMedID 3763603
Pathway specific and differential effects produced by halothane on hippocampal neurons in vitro.
Proceedings of the Western Pharmacology Society
1986; 29: 163-166
View details for PubMedID 3763604
- THE EFFECTS OF TEMPERATURE ON NEURONAL EXCITABILITY PROCEEDINGS OF THE WESTERN PHARMACOLOGY SOCIETY 1982; 25: 427-431
A SIMPLE AND SENSITIVE FORCE TRANSDUCER SUITABLE FOR MEASURING TENSIONS IN SMALL MUSCLE-FIBERS
JOURNAL OF PHARMACOLOGICAL METHODS
1981; 5 (2): 93-98
The design and fabrication of a simple tension force transducer, sensitive enough to measure tensions of individual and fine bundles of muscle fibers, is described. The transducer is capable of accurately measuring tensions as little as 0.5 dynes along the longitudinal axis of fibers. The response of the transducer is linear within the range of 0.5 to 500 dynes. Examples of its use and small crustacean striated and vertebrate cardiac muscle fibers are presented.
View details for Web of Science ID A1981LG93100001
View details for PubMedID 6971964
- EFFECTS OF HALOTHANE ON THE NEURONAL OUTPUT, MEMBRANE-PROPERTIES AND SYNAPTIC TRANSMISSION OF AN ISOLATED NEURON PROCEEDINGS OF THE WESTERN PHARMACOLOGY SOCIETY 1980; 23: 405-411