ArticleThe international journal of neuropsychopharmacology2019
(R)-Ketamine Induces a Greater Increase in Prefrontal 5-HT Release Than (S)-Ketamine and Ketamine Metabolites via an AMPA Receptor-Independent Mechanism.
Article in The international journal of neuropsychopharmacology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 2 of them syntheses that pooled it.
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Who cites it
43 citing papers in PubMed, 2 syntheses or guidelines pooled it, 89 citations in OpenAlex.
- Can ketamine and other glutamate receptor modulators be considered entactogens?Psychiatry research · 2025Pooled it
- Ketamine treatment for refractory anxiety: A systematic review.British journal of clinical pharmacology · 2022Pooled it
- Effect of esketamine on serum neurotransmitters in patients with postpartum depression: a randomized controlled trial.BMC anesthesiology · 2024Trial
- Pleiotropic modulation of the gut-brain-lung axis by ketamine and its enantiomers.Molecular psychiatry · 2026Review
- Ketamine attenuates anxiety-like behavior and oxidative imbalance in the maternal immune activation model: emphasis on the cerebellum.Psychopharmacology · 2026Article
- Review
- Efficacy of Oral Ketamine in Patients with Depression and Suicidality: A Retrospective Study.Indian journal of psychological medicine · 2026Article
- Mechanism of antidepressant action of ketamine and differences between its two enantiomers.Journal of anesthesia and translational medicine · 2025Review
- Insomnia and Esketamine Add-On Therapy to Antidepressant Therapy in Patients with Treatment-Resistant Depression-A Pilot Study.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Ketamine in clinical practice: transitioning from anesthetic agent to psychiatric therapeutic.CNS spectrums · 2025Review
- Enduring modulation of dorsal raphe nuclei regulates (R,S)-ketamine-mediated resilient stress-coping behavior.Molecular psychiatry · 2025Article
- Prophylactic (R,S)-Ketamine and (2S,6S)-Hydroxynorketamine Decrease Fear Expression by Differentially Modulating Fear Neural Ensembles.Biological psychiatry · 2025Article
- Perspectives in treatment-resistant depression: esketamine and electroconvulsive therapy.Wiener klinische Wochenschrift · 2025Review
- (R)-ketamine restores anterior insular cortex activity and cognitive deficits in social isolation-reared mice.Molecular psychiatry · 2024Article
- Unique Effects of (R)-Ketamine Compared to (S)-Ketamine on EEG Theta Power in Rats.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Psychopharmacological Approaches for Neural Plasticity and Neurogenesis in Major Depressive Disorders.Advances in experimental medicine and biology · 2024Review
- Exploring the multifaceted potential of (R)-ketamine beyond antidepressant applications.Frontiers in pharmacology · 2024Review
- Limbic System Response to Psilocybin and Ketamine Administration in Rats: A Neurochemical and Behavioral Study.International journal of molecular sciences · 2023Article
- (R)-ketamine attenuates neurodevelopmental disease-related phenotypes in a mouse model of maternal immune activation.European archives of psychiatry and clinical neuroscience · 2023Article
- (S)-Ketamine but Not (R)-Ketamine Shows Acute Effects on Depression-Like Behavior and Sleep-Wake Architecture in Rats.The international journal of neuropsychopharmacology · 2023Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAlthough recent studies provide insight into the molecular mechanisms of the effects of ketamine, the antidepressant mechanism of ketamine enantiomers and their metabolites is not fully understood. In view of the involvement of mechanisms other than the N-methyl-D-aspartate receptor in ketamine's action, we investigated the effects of (R)-ketamine, (S)-ketamine, (R)-norketamine [(R)-NK], (S)-NK, (2R,6R)-hydroxynorketamine [(2R,6R)-HNK], and (2S,6S)-HNK on monoaminergic neurotransmission in the prefrontal cortex of mice.
methodsThe extracellular monoamine levels in the prefrontal cortex were measured by in vivo microdialysis.
results(R)-Ketamine and (S)-ketamine acutely increased serotonin release in a dose-dependent manner, and the effect of (R)-ketamine was greater than that of (S)-ketamine. In contrast, (S)-ketamine caused a robust increase in dopamine release compared with (R)-ketamine. Both ketamine enantiomers increased noradrenaline release, but these effects did not differ. (2R,6R)-HNK caused a slight but significant increase in serotonin and noradrenaline but not dopamine release. (S)-NK increased dopamine and noradrenaline but not serotonin release. Differential effects between (R)-ketamine and (S)-ketamine were also observed in a lipopolysaccharide-induced model of depression. An α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4- tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), attenuated (S)-ketamine-induced, but not (R)-ketamine-induced serotonin release, whereas NBQX blocked dopamine release induced by both enantiomers. Local application of (R)-ketamine into the prefrontal cortex caused a greater increase in prefrontal serotonin release than that of (S)-ketamine.
conclusions(R)-Ketamine strongly activates the prefrontal serotonergic system through an AMPA receptor-independent mechanism. (S)-Ketamine-induced serotonin and dopamine release was AMPA receptor-dependent. These findings provide a neurochemical basis for the underlying pharmacological differences between ketamine enantiomers and their metabolites.
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Registered trials
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