ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2020
Sex-specific neurobiological actions of prophylactic (R,S)-ketamine, (2R,6R)-hydroxynorketamine, and (2S,6S)-hydroxynorketamine.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 69 citations in OpenAlex.
- A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.Clinical pharmacology and therapeutics · 2024Trial
- Sex-dependent metabolism of ketamine and (Journal of psychopharmacology (Oxford, England) · 2022Trial
- The role of BDNF promoter VI in mediating protective effects of prophylactic (R,S)-ketamine.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Bifunctional Modulation of NMDA and Opioid Receptors in Ketamine Reinforcement and Misuse: Implications for Substance Use Disorder Treatment.Biological psychiatry · 2026Review
- Sex, drugs, and arousal-two randomized trials on the effects of ketamine on sexual arousal and calcarine gyrus activity.Therapeutic advances in psychopharmacology · 2026Article
- Novel, small molecules targeting the 5-HTbioRxiv : the preprint server for biology · 2025Article
- Mechanism of antidepressant action of ketamine and differences between its two enantiomers.Journal of anesthesia and translational medicine · 2025Review
- Sex-Specific Neuropsychiatric Effects of Subanesthetic Ketamine Exposure in Pregnant Mice and Their Offspring.Cellular and molecular neurobiology · 2025Article
- Combinatorial targeting of NMDARs and 5-HTAlzheimer's research & therapy · 2025Article
- Chronic, combinatorial targeting of NMDARs and 5-HTNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Enduring modulation of dorsal raphe nuclei regulates (R,S)-ketamine-mediated resilient stress-coping behavior.Molecular psychiatry · 2025Article
- Ketamine and Hydroxynorketamine: The Complex Balancing Act Within Fear Neural Ensembles.Biological psychiatry · 2025Article
- Prophylactic (R,S)-Ketamine and (2S,6S)-Hydroxynorketamine Decrease Fear Expression by Differentially Modulating Fear Neural Ensembles.Biological psychiatry · 2025Article
- Mapping Fear-Related Neural Activity and Circuitry Changes Following Prophylactic Administration of (R,S)-Ketamine and (2S,6S)-Hydroxynorketamine.Neuroscience bulletin · 2025Article
- Rapid hippocampal synaptic potentiation induced by ketamine metabolite (2R,6R)-hydroxynorketamine persistently primes synaptic plasticity.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Psychedelic Drugs in Mental Disorders: Current Clinical Scope and Deep Learning-Based Advanced Perspectives.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- GluN2B on Adult-Born Granule Cells Modulates (R,S)-Ketamine's Rapid-Acting Effects in Mice.The international journal of neuropsychopharmacology · 2024Article
- Hydroxynorketamine, but not ketamine, acts via α7 nicotinic acetylcholine receptor to control presynaptic function and gene expression.Translational psychiatry · 2024Article
- Comparing the adverse effects of ketamine and esketamine between genders using FAERS data.Frontiers in pharmacology · 2024Article
- Whole-brain mapping reveals the divergent impact of ketamine on the dopamine system.Cell reports · 2023Article
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 2 countries.
Funding
Abstract
Enhancing stress resilience in at-risk populations could significantly reduce the incidence of stress-related psychiatric disorders. We have previously reported that the administration of (R,S)-ketamine prevents stress-induced depressive-like behavior in male mice, perhaps by altering α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission in hippocampal CA3. However, it is still unknown whether metabolites of (R,S)-ketamine can be prophylactic in both sexes. We administered (R,S)-ketamine or its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-hydroxynorketamine ((2S,6S)-HNK) at various doses 1 week before one of a number of stressors in male and female 129S6/SvEv mice. Patch clamp electrophysiology was used to determine the effect of prophylactic drug administration on glutamatergic activity in CA3. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy (OVX) surgery and a hormone replacement protocol prior to drug administration. (2S,6S)-HNK and (2R,6R)-HNK protected against distinct stress-induced behaviors in both sexes, with (2S,6S)-HNK attenuating learned fear in male mice, and (2R,6R)-HNK preventing stress-induced depressive-like behavior in both sexes. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, attenuated large-amplitude AMPAR-mediated bursts in hippocampal CA3. All three compounds reduced N-methyl-D-aspartate receptor (NMDAR)-mediated currents 1 week after administration. Furthermore, ovarian-derived hormones were necessary for and sufficient to restore (R,S)-ketamine- and (2R,6R)-HNK-mediated prophylaxis in female mice. Our data provide further evidence that resilience-enhancing prophylactics may alter AMPAR-mediated glutamatergic transmission in CA3. Moreover, we show that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and demonstrate that ovarian hormones are necessary for the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-HNK in female mice.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.