Austen Brooks Casey

All Publications

• The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation. Nature neuroscience Aarrestad, I. K., Cameron, L. P., Fenton, E. M., Casey, A. B., Rijsketic, D. R., Patel, S. D., Sambyal, R., Johnson, S. B., Ly, C., Viswanathan, J., Barragan, E. V., Lozano, S. A., Seban, N., Hu, H., Powell, N. A., Chytil, M., Meyer, R., Rose, D., Hempel, C., Olson, E., Hansen, H. D., Madsen, C. A., Knudsen, G. M., Redd, C., Wheeler, D. G., Guanzon, N., Muir, J., Hennessey, J. J., Quon, G., McCorvy, J. D., Gandhi, S. P., Rasmussen, K., Liston, C., Gray, J. A., Heifets, B. D., Nord, A. S., Kim, C. K., Olson, D. E. 2025

  Abstract

  Nonhallucinogenic psychoplastogens, such as tabernanthalog (TBG), are being developed as potentially safer, more scalable alternatives to psychedelics for promoting neuronal growth and treating various brain conditions. Currently, it is unclear whether 5-hydroxytryptamine 2A (5-HT2A) receptors and immediate early gene (IEG) activation have a role in the neuroplasticity-promoting effects of nonhallucinogenic psychoplastogens. Here, we use pharmacological and genetic tools in rodents to show that nonhallucinogenic psychoplastogens promote cortical neuroplasticity through the same biochemical pathway-involving 5-HT2A, TrkB, mTOR and AMPA receptor activation-as classic psychedelics and that TBG-induced cortical spinogenesis is required for the sustained antidepressant-like behavioral effect of TBG. In contrast to psychedelics, TBG does not induce an immediate glutamate burst or IEG activation. As these effects have been assumed to be necessary for psychedelic-induced neuroplasticity, our results shed light on the mechanisms by which certain psychoplastogens can promote cortical neuroplasticity in the absence of hallucinogenic effects.

  View details for DOI 10.1038/s41593-025-02021-1

  View details for PubMedID 40760185

• 5-HT2C receptors in the nucleus accumbens constrain the rewarding effects of MDMA. Molecular psychiatry Pomrenze, M. B., Vaillancourt, S., Salgado, J. S., Raymond, K. B., Llorach, P., Sacai, H., Rijsketic, D. R., Hietamies, T. M., Touponse, G. C., Cardozo Pinto, D. F., Rastegar, Z., Casey, A. B., Eshel, N., Malenka, R. C., Heifets, B. D. 2025

  Abstract

  MDMA is a promising adjunct to psychotherapy and has well-known abuse liability, although less than other amphetamine analogs. While the reinforcing dopamine (DA)-releasing properties of MDMA are on par with methamphetamine (METH), MDMA is a far more potent serotonin (5-HT) releaser, via the 5-HT transporter (SERT). MDMA-mediated 5-HT release in a major reward center, the nucleus accumbens (NAc), drives prosocial behaviors via 5-HT1BR activation. We hypothesized that this prosocial mechanism contributes to the reduced reinforcing properties of MDMA compared to METH and used a platform of assays to predict the balance of prosocial and abuse-linked effects of (R)-MDMA, a novel entactogen in clinical development. NAc DA release, measured by GRAB-DA photometry in vivo, increased in proportion to MDMA (7.5 and 15 mg/kg, i.p.) and METH (2 mg/kg i.p.)-conditioned place preference (CPP). Using conditional knockouts (cKOs) for DAT and SERT, microdialysis, and photometry, we found that MDMA-released 5-HT limited MDMA-released DA through actions in the NAc, rather than at ventral tegmental area DAergic cell bodies. SERT cKO reduced the MDMA dose required for CPP three-fold. This enhanced MDMA-CPP and increased DA release were replicated by intra-NAc infusion of either a 5-HT reuptake inhibitor (escitalopram) to prevent MDMA interaction with SERT, or a 5-HT2CR antagonist (SB242084), but not by the 5-HT1BR antagonist NAS-181. These data support separate mechanisms for the low abuse potential versus prosocial effect of MDMA. Using this platform of assays, (R)-MDMA is predicted to have prosocial effects and low abuse potential.

  View details for DOI 10.1038/s41380-025-03128-4

  View details for PubMedID 40707786

  View details for PubMedCentralID 3065181

• Ketamine evokes acute behavioral effects via μ-opioid receptor expressing neurons of the central amygdala. Biological psychiatry Pomrenze, M. B., Vaillancourt, S., Llorach, P., Rijsketic, D. R., Casey, A. B., Gregory, N., Zhao, W., Girard, T. E., Mattox, K. T., Salgado, J. S., Malenka, R. C., Heifets, B. D. 2025

  Abstract

  Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. This mechanism may differentiate ketamine from other NMDA receptor antagonists. Animal models that reflect OR-dependent behavioral effects of ketamine may shed light on the brain regions and circuits that contribute to ketamine's antidepressant mechanism in humans.We screened male and female wild-type mice for a behavioral response to ketamine that could be reversed by OR antagonists in several assays, including locomotor activation, analgesia, and the forced swim test. Whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, was used to identify brain areas mediating ketamine / OR interactions. Region-specific pharmacological and genetic interference with μOR (MOR) signaling was used to test predictions of whole-brain imaging results in a subset of behavioral assays.Among a series of behavioral assays, only locomotor-activation was sensitive to ketamine and blocked by an MOR-selective antagonist. Locomotor activation produced by the NMDA receptor antagonist, MK-801, was not OR-dependent. Whole-brain imaging revealed cFos expression in neurons of the central amygdala (CeA) showed the greatest difference between ketamine in the presence versus absence of naltrexone. CeA neurons expressing both MOR and PKCδ were strongly activated by naltrexone, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine.These data suggest that ketamine acts at MORs expressed in CeA neurons to produce acute hyperlocomotion.

  View details for DOI 10.1016/j.biopsych.2025.04.020

  View details for PubMedID 40334963

• Psilocybin Has No Analgesic Properties in Multiple Mouse Models of Acute and Chronic Pain Gregory, N. S., Girard, T. E., Ram, A., Casey, A. B., Malenka, R. C., Tawfik, V. L., Heifets, B. D. CHURCHILL LIVINGSTONE. 2025

  View details for DOI 10.1016/j.jpain.2025.104862

  View details for Web of Science ID 001498970500049

• Neural Circuit Delineation of (±)-3,4-methylenedioxymethamphetamine (MDMA)-evoked Sociability and Fear Memory Deficits Casey, A., Rijsketic, D., Zhao, W., Palmer, A., Salgado, J., Llorach, P., Wall, N., Pomrenze, M., Malenka, R., Heifets, B. ELSEVIER SCIENCE INC. 2024: S254

  View details for Web of Science ID 001282811900602

• Anesthesia as a Control for Blinding in Psychedelic Therapy Hietamies, T., Casey, A., Zhao, W., Rijsketic, D., Deverett, B., Restagar, Z., Heifets, B. ELSEVIER SCIENCE INC. 2024: S199

  View details for Web of Science ID 001282811900467

• Opioid receptor expressing neurons of the central amygdala gate behavioral effects of ketamine in mice. bioRxiv : the preprint server for biology Pomrenze, M. B., Vaillancourt, S., Llorach, P., Rijsketic, D. R., Casey, A. B., Gregory, N., Salgado, J. S., Malenka, R. C., Heifets, B. D. 2024

  Abstract

  Ketamine has anesthetic, analgesic, and antidepressant properties which may involve multiple neuromodulatory systems. In humans, the opioid receptor (OR) antagonist naltrexone blocks the antidepressant effect of ketamine. It is unclear whether naltrexone blocks a direct effect of ketamine at ORs, or whether normal functioning of the OR system is required to realize the full antidepressant effects of treatment. In mice, the effect of ketamine on locomotion, but not analgesia or the forced swim test, was sensitive to naltrexone and was therefore used as a behavioral readout to localize the effect of naltrexone in the brain. We performed whole-brain imaging of cFos expression in ketamine-treated mice, pretreated with naltrexone or vehicle, and identified the central amygdala (CeA) as the area with greatest difference in cFos intensity. CeA neurons expressing both μOR (MOR) and PKCμ were strongly activated by naltrexone but not ketamine, and selectively interrupting MOR function in the CeA either pharmacologically or genetically blocked the locomotor effects of ketamine. These data suggest that MORs expressed in CeA neurons gate behavioral effects of ketamine but are not direct targets of ketamine.

  View details for DOI 10.1101/2024.03.03.583196

  View details for PubMedID 38496451

  View details for PubMedCentralID PMC10942405

• UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Rijsketic, D. R., Casey, A. B., Barbosa, D. A., Zhang, X., Hietamies, T. M., Ramirez-Ovalle, G., Pomrenze, M. B., Halpern, C. H., Williams, L. M., Malenka, R. C., Heifets, B. D. 2023

  Abstract

  The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged iDISCO+ cleared tissue with light sheet fluorescence microscopy (LSFM) to examine the impact of environmental context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed clusters of neural activity associated with main effects of context and psilocybin-treatment, which were validated with c-Fos+ cell density measurements. Psilocybin increased c-Fos expression in subregions of the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus while it decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum in a predominantly context-independent manner. To gauge feasibility of future mechanistic studies on ensembles activated by psilocybin, we confirmed activity- and Cre-dependent genetic labeling in a subset of these neurons using TRAP2+/-;Ai14+ mice. Network analyses treating each psilocybin-sensitive cluster as a node indicated that psilocybin disrupted co-activity between highly correlated regions, reduced brain modularity, and dramatically attenuated intermodular co-activity. Overall, our results indicate that main effects of context and psilocybin were robust, widespread, and reorganized network architecture, whereas context×psilocybin interactions were surprisingly sparse.

  View details for DOI 10.1038/s41386-023-01613-4

  View details for PubMedID 37248402

  View details for PubMedCentralID 7007572

• Brain-Wide Activity Mapping Reveals a Required Role for the Dorsal Endopiriform Nucleus in MDMA-Evoked Prosocial Behavior Heifets, B., Rijsketic, D., Salgado, J., Wall, N., Ramirez-Ovalle, G., Llorach, P., Lopez, R., Casey, A., Hietamies, T., Rastegar, Z., Barbosa, D., Beier, K., Malenka, R. ELSEVIER SCIENCE INC. 2023: S57-S58

  View details for Web of Science ID 000993018500139

• UNRAVELing the synergistic effects of psilocybin and environment on brain-wide immediate early gene expression in mice. bioRxiv : the preprint server for biology Rijsketic, D. R., Casey, A. B., Barbosa, D. A., Zhang, X., Hietamies, T. M., Ramirez-Ovalle, G., Pomrenze, M., Halpern, C. H., Williams, L. M., Malenka, R. C., Heifets, B. D. 2023

  Abstract

  The effects of context on the subjective experience of serotonergic psychedelics have not been fully examined in human neuroimaging studies, partly due to limitations of the imaging environment. Here, we administered saline or psilocybin to mice in their home cage or an enriched environment, immunofluorescently-labeled brain-wide c-Fos, and imaged cleared tissue with light sheet microscopy to examine the impact of context on psilocybin-elicited neural activity at cellular resolution. Voxel-wise analysis of c-Fos-immunofluorescence revealed differential neural activity, which we validated with c-Fos + cell density measurements. Psilocybin increased c-Fos expression in the neocortex, caudoputamen, central amygdala, and parasubthalamic nucleus and decreased c-Fos in the hypothalamus, cortical amygdala, striatum, and pallidum. Main effects of context and psilocybin-treatment were robust, widespread, and spatially distinct, whereas interactions were surprisingly sparse.

  View details for DOI 10.1101/2023.02.19.528997

  View details for PubMedID 36865251

  View details for PubMedCentralID PMC9980055

• "Selective" serotonin 5-HT2A receptor antagonists. Biochemical pharmacology Casey, A. B., Cui, M., Booth, R. G., Canal, C. E. 2022: 115028

  Abstract

  Blockade of the serotonin 5-HT2A G protein-coupled receptor (5-HT2AR) is a fundamental pharmacological characteristic of numerous antipsychotic medications, which are FDA-approved to treat schizophrenia, bipolar disorder, and as adjunctive therapies in major depressive disorder. Meanwhile, activation of the 5-HT2AR by serotonergic psychedelics may be useful in treating neuropsychiatric indications, including major depressive and substance use disorders. Serotonergic psychedelics and other 5-HT2AR agonists, however, often bind other receptors, and standard 5-HT2AR antagonists lack sufficient selectivity to make well-founded mechanistic conclusions about the 5-HT2AR-dependent effects of these compounds and the general neurobiological function of 5-HT2ARs. This review discusses the limitations and strengths of currently available "selective" 5-HT2AR antagonists, the molecular determinants of antagonist selectivity at 5-HT2ARs, and the utility of molecular pharmacological and computational methods in guiding the discovery of novel unambiguously selective 5-HT2AR antagonists.

  View details for DOI 10.1016/j.bcp.2022.115028

  View details for PubMedID 35381208

• A new class of serotonin 5-HT2A/5-HT2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2-aminotetralins British Journal of Pharacology Casey, A. B., Mukherjee, M., McGlynn, R. P., Cui, M., Kohut, S. J., Booth, R. G. 2021

  View details for DOI 10.1111/bph.15756

• (S)-5-(2 '-Fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE Armstrong, J. L., Casey, A. B., Saraf, T. S., Mukherjee, M., Booth, R. G., Canal, C. E. 2020; 3 (3): 509-523

  Abstract

  Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disabilities and a plethora of neuropsychiatric symptoms. FXS is the leading monogenic cause of autism spectrum disorder (ASD), which is defined clinically by repetitive and/or restrictive patterns of behavior and social communication deficits. Epilepsy and anxiety are also common in FXS and ASD. Serotonergic neurons directly innervate and modulate the activity of neurobiological circuits altered in both disorders, providing a rationale for investigating serotonin receptors (5-HTRs) as targets for FXS and ASD drug discovery. Previously we unveiled an orally active aminotetralin, (S)-5-(2'-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine (FPT), that exhibits partial agonist activity at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs and that reduces repetitive behaviors and increases social approach behavior in wild-type mice. Here we report that in an Fmr1 knockout mouse model of FXS and ASD, FPT is prophylactic for audiogenic seizures. No FPT-treated mice displayed audiogenic seizures, compared to 73% of vehicle-treated mice. FPT also exhibits anxiolytic-like effects in several assays and increases social interactions in both Fmr1 knockout and wild-type mice. Furthermore, FPT increases c-Fos expression in the basolateral amygdala, which is a preclinical effect produced by anxiolytic medications. Receptor pharmacology assays show that FPT binds competitively and possesses rapid association and dissociation kinetics at 5-HT1ARs and 5-HT7Rs, yet has slow association and rapid dissociation kinetics at 5-HT2CRs. Finally, we reassessed and report FPT's affinity and function at 5-HT1ARs, 5-HT2CRs, and 5-HT7Rs. Collectively, these observations provide mounting support for further development of FPT as a pharmacotherapy for common neuropsychiatric symptoms in FXS and ASD.

  View details for DOI 10.1021/acsptsci.9b00101

  View details for Web of Science ID 000604267300012

  View details for PubMedID 32566916

  View details for PubMedCentralID PMC7296548

• Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling BIOORGANIC & MEDICINAL CHEMISTRY Perry, C. K., Casey, A. B., Felsing, D. E., Vemula, R., Zaka, M., Herrington, N. B., Cui, M., Kellogg, G. E., Canal, C. E., Booth, R. G. 2020; 28 (3): 115262

  Abstract

  The serotonin 5-HT7 G protein-coupled receptor (GPCR) is a proposed pharmacotherapeutic target for a variety of central and peripheral indications, albeit, there are no approved drugs selective for binding 5-HT7. We previously reported that a lead analog based on the 5-substituted-N,N-disubstituted-1,2,3,4-tetrahydronaphthalen-2-amine (5-substituted-2-aminotetralin, 5-SAT) scaffold binds with high affinity at the 5-HT7 GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT1A GPCR. Herein, we report the synthesis of novel 5-SAT analogs to develop a 3-dimensional quantitative structure-affinity relationship (3D-QSAR) at the human 5-HT7 receptor for comparison with similar studies at the highly homologous 5-HT1A receptor. We report 35 new 5-SAT ligands, some with very high affinity (Ki ≤ 1 nM) and stereoselectivity at 5-HT7 + or 5-HT1A receptors, several with modest selectivity (up to 12-fold) for binding at 5-HT7, and, several ligands with high selectivity (up to 40-fold) at the 5-HT1A receptor. 3D-QSAR results indicate that steric extensions at the C(5)-position improve selectivity for the 5-HT7 over 5-HT1A receptor, while steric and hydrophobic extensions at the chiral C(2)-amino position impart 5-HT1A selectivity. In silico receptor homology modeling studies, supplemented with molecular dynamics simulations and binding free energy calculations, were used to rationalize experimentally-determined receptor selectivity and stereoselective affinity results. The data from these studies indicate that the 5-SAT chemotype, previously shown to be safe and efficacious in rodent paradigms of neurodevelopmental and neuropsychiatric disorders, is amenable to structural modification to optimize affinity at serotonin 5-HT7 vs. 5-HT1A GPCRs, as may be required for successful clinical translation.

  View details for DOI 10.1016/j.bmc.2019.115262

  View details for Web of Science ID 000507466200009

  View details for PubMedID 31882369

• Classics in Chemical Neuroscience: Aripiprazole ACS CHEMICAL NEUROSCIENCE Casey, A. B., Canal, C. E. 2017; 8 (6): 1135-1146

  Abstract

  Aripiprazole was the first antipsychotic developed to possess agonist properties at dopamine D2 autoreceptors, a groundbreaking strategy that presented a new vista for schizophrenia drug discovery. The dopamine D2 receptor is the crucial target of all extant antipsychotics, and all developed prior to aripiprazole were D2 receptor antagonists. Extensive blockade of these receptors, however, typically produces extrapyramidal (movement) side effects, which plagued first-generation antipsychotics, such as haloperidol. Second-generation antipsychotics, such as clozapine, with unique polypharmacology and D2 receptor binding kinetics, have significantly lower risk of movement side effects but can cause myriad additional ones, such as severe weight gain and metabolic dysfunction. Aripiprazole's polypharmacology, characterized by its unique agonist activity at dopamine D2 and D3 and serotonin 5-HT1A receptors, as well as antagonist activity at serotonin 5-HT2A receptors, translates to successful reduction of positive, negative, and cognitive symptoms of schizophrenia, while also mitigating risk of weight gain and movement side effects. New observations, however, link aripiprazole to compulsive behaviors in a small group of patients, an unusual side effect for antipsychotics. In this review, we discuss the chemical synthesis, pharmacology, pharmacogenomics, drug metabolism, and adverse events of aripiprazole, and we present a current understanding of aripiprazole's neurotherapeutic mechanisms, as well as the history and importance of aripiprazole to neuroscience.

  View details for DOI 10.1021/acschemneuro.7b00087

  View details for Web of Science ID 000404098100004

  View details for PubMedID 28368577

  View details for PubMedCentralID PMC5495458