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Research Articles, Neurobiology of Disease

NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine

Panos Zanos, Kyle A. Brown, Polymnia Georgiou, Peixiong Yuan, Carlos A. Zarate Jr, Scott M. Thompson and Todd D. Gould
Journal of Neuroscience 8 February 2023, 43 (6) 1038-1050; DOI: https://doi.org/10.1523/JNEUROSCI.1316-22.2022
Panos Zanos
1Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland 21201
2Department of Psychology, University of Cyprus, Nicosia 2109, Cyprus
5Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland 21201
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Kyle A. Brown
1Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland 21201
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Polymnia Georgiou
1Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland 21201
3Department of Biology, University of Cyprus, Nicosia 2109, Cyprus
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Peixiong Yuan
4Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
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Carlos A. Zarate Jr
4Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892
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Scott M. Thompson
1Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland 21201
5Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland 21201
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Todd D. Gould
1Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, Maryland 21201
6Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, Maryland 21201
7Department of Anatomy & Neurobiology, School of Medicine, University of Maryland, Baltimore, Maryland 21201
8Veterans Affairs Maryland Health Care System, Baltimore, Maryland 21201
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Abstract

Ketamine is a well-characterized NMDA receptor (NMDAR) antagonist, although the relevance of this pharmacology to its rapid (within hours of administration) antidepressant actions, which depend on mechanisms convergent with strengthening of excitatory synapses, is unclear. Activation of synaptic NMDARs is necessary for the induction of canonical long-term potentiation (LTP) leading to a sustained expression of increased synaptic strength. We tested the hypothesis that induction of rapid antidepressant effects requires NMDAR activation, by using behavioral pharmacology, western blot quantification of hippocampal synaptoneurosomal protein levels, and ex vivo hippocampal slice electrophysiology in male mice. We found that ketamine exerts an inverted U-shaped dose-response in antidepressant-sensitive behavioral tests, suggesting that an excessive NMDAR inhibition can prevent ketamine's antidepressant effects. Ketamine's actions to induce antidepressant-like behavioral effects, up-regulation of hippocampal AMPAR subunits GluA1 and GluA2, as well as metaplasticity measured ex vivo using electrically-stimulated LTP, were abolished by pretreatment with other non-antidepressant NMDAR antagonists, including MK-801 and CPP. Similarly, the antidepressant-like actions of other putative rapid-acting antidepressant drugs (2R,6R)-hydroxynorketamine (ketamine metabolite), MRK-016 (GABAAα5 negative allosteric modulator), and LY341495 (mGlu2/3 receptor antagonist) were blocked by NMDAR inhibition. Ketamine acted synergistically with an NMDAR positive allosteric modulator to exert antidepressant-like behavioral effects and activation of the NMDAR subunit GluN2A was necessary and sufficient for such relevant effects. We conclude rapid-acting antidepressant compounds share a common downstream NMDAR-activation dependent effector mechanism, despite variation in initial pharmacological targets. Promoting NMDAR signaling or other approaches that enhance NMDAR-dependent LTP-like synaptic potentiation may be an effective antidepressant strategy.

SIGNIFICANCE STATEMENT The anesthetic and antidepressant drug ketamine is well-characterized as an NMDA receptor (NMDAR) antagonist; though, the relevance and full impact of this pharmacology to its antidepressant actions is unclear. We found that NMDAR activation, which occurs downstream of their initial actions, is necessary for the beneficial effects of ketamine and several other putative antidepressant compounds. As such, promoting NMDAR signaling, or other approaches that enhance NMDAR-dependent long-term potentiation (LTP)-like synaptic potentiation in vivo may be an effective antidepressant strategy directly, or acting synergistically with other drug or interventional treatments.

  • AMPA receptor
  • antidepressant
  • hydroxynorketamine
  • ketamine
  • LTP
  • NMDA receptor

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The Journal of Neuroscience: 43 (6)
Journal of Neuroscience
Vol. 43, Issue 6
8 Feb 2023
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NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine
Panos Zanos, Kyle A. Brown, Polymnia Georgiou, Peixiong Yuan, Carlos A. Zarate Jr, Scott M. Thompson, Todd D. Gould
Journal of Neuroscience 8 February 2023, 43 (6) 1038-1050; DOI: 10.1523/JNEUROSCI.1316-22.2022

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NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine
Panos Zanos, Kyle A. Brown, Polymnia Georgiou, Peixiong Yuan, Carlos A. Zarate Jr, Scott M. Thompson, Todd D. Gould
Journal of Neuroscience 8 February 2023, 43 (6) 1038-1050; DOI: 10.1523/JNEUROSCI.1316-22.2022
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Keywords

  • AMPA receptor
  • antidepressant
  • hydroxynorketamine
  • ketamine
  • LTP
  • NMDA receptor

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