AMPA Receptor Activation-Independent Antidepressant Actions of Ketamine Metabolite (S)-Norketamine.
Chun Yang, Shizuka Kobayashi, Kazuhito Nakao, Chao Dong, Mei Han, Youge Qu, Qian Ren, Ji-Chun Zhang, Min Ma, Hidetoh Toki, Jun-Ichi Yamaguchi, Shigeyuki Chaki, Yukihiko Shirayama, Kazu Nakazawa, Toshiya Manabe, Kenji Hashimoto
Biological Psychiatry October 15, 2018 DOI: 10.1016/j.biopsych.2018.05.007 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice, including inflammation and chronic social defeat stress models |
| Interventions | (S)-norketamine (R)-norketamine |
| Topics | Esketamine Ketamine |
| Keywords | Ampar Antidepressant Bdnf Nmdar Norketamine |
| Key points | Argues that (S)-norketamine has more potent antidepressant and synaptic benefits than (R)-norketamine in mice, acting through a mechanism independent of AMPA receptor activation but dependent on BDNF-TrkB and mTOR signaling, and without the behavioral side effects seen with (S)-ketamine. |
Abstract
Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts robust antidepressant effects in patients with treatment-resistant depression. The precise mechanisms underlying ketamine's antidepressant actions remain unclear, although previous research suggests that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) activation plays a role. We investigated whether (S)-norketamine and (R)-norketamine, the two main metabolites of (R,S)-ketamine, also play a significant role in ketamine's antidepressant effects and whether the effects are mediated by AMPAR. Cellular mechanisms of antidepressant action of norketamine enantiomers were examined in mice. (S)-Norketamine had more potent antidepressant effects than (R)-norketamine in inflammation and chronic social defeat stress models. Furthermore, (S)-norketamine induced more beneficial effects on decreased dendritic spine density and synaptogenesis in the prefrontal cortex and hippocampus compared with (R)-norketamine. Unexpectedly, AMPAR antagonists did not block the antidepressant effects of (S)-norketamine. The electrophysiological data showed that, although (S)-norketamine inhibited N-methyl-D-aspartate receptor-mediated synaptic currents, (S)-norketamine did not enhance AMPAR-mediated neurotransmission in hippocampal neurons. Furthermore, (S)-norketamine improved reductions in brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling in the prefrontal cortex of mice susceptible to chronic social defeat stress, whereas the tropomyosin receptor kinase B antagonist and a mechanistic target of rapamycin inhibitor blocked the antidepressant effects of (S)-norketamine. In contrast to (S)-ketamine, (S)-norketamine did not cause behavioral abnormalities, such as prepulse inhibition deficits, reward effects, loss of parvalbumin immunoreactivity in the medial prefrontal cortex, or baseline gamma-band oscillation increase. Our data identified a novel AMPAR activation-independent mechanism underlying the antidepressant effects of (S)-norketamine. (S)-Norketamine and its prodrugs could be novel antidepressants without the detrimental side effects of (S)-ketamine.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 57
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Role of BDNF in the pathophysiology and treatment of depression: Activity‐dependent effects distinguish rapid‐acting antidepressants European Journal of Neuroscience December 6, 2019
- Ketamine: A tale of two enantiomers Journal of Psychopharmacology November 6, 2020
- Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor Molecular Psychiatry May 7, 2021
- Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochemical Pharmacology July 1, 2020
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Cites 29
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and 24 more in the library