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Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6441-6450. doi: 10.1073/pnas.1819540116. Epub 2019 Mar 13.

(2R,6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions.

Author information

1
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201.
2
Program in Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201.
3
Biomedical Research Center, National Institute on Aging, NIH, Baltimore, MD 21224.
4
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20892.
5
Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, MD 20892.
6
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201; gouldlab@me.com.
7
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201.
8
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201.
9
Veterans Affairs Maryland Health Care System, Baltimore, MD 21201.

Abstract

Currently approved antidepressant drugs often take months to take full effect, and ∼30% of depressed patients remain treatment resistant. In contrast, ketamine, when administered as a single subanesthetic dose, exerts rapid and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant drug candidate with limited dissociation properties and abuse potential. We assessed the role of group II metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) in the antidepressant-relevant actions of (2R,6R)-HNK using behavioral, genetic, and pharmacological approaches as well as cortical quantitative EEG (qEEG) measurements in mice. Both ketamine and (2R,6R)-HNK prevented mGlu2/3 receptor agonist (LY379268)-induced body temperature increases in mice lacking the Grm3, but not Grm2, gene. This action was not replicated by NMDA receptor antagonists or a chemical variant of ketamine that limits metabolism to (2R,6R)-HNK. The antidepressant-relevant behavioral effects and 30- to 80-Hz qEEG oscillation (gamma-range) increases resultant from (2R,6R)-HNK administration were prevented by pretreatment with an mGlu2/3 receptor agonist and absent in mice lacking the Grm2, but not Grm3 -/-, gene. Combined subeffective doses of the mGlu2/3 receptor antagonist LY341495 and (2R,6R)-HNK exerted synergistic increases on gamma oscillations and antidepressant-relevant behavioral actions. These findings highlight that (2R,6R)-HNK exerts antidepressant-relevant actions via a mechanism converging with mGlu2 receptor signaling and suggest enhanced cortical gamma oscillations as a marker of target engagement relevant to antidepressant efficacy. Moreover, these results support the use of (2R,6R)-HNK and inhibitors of mGlu2 receptor function in clinical trials for treatment-resistant depression either alone or in combination.

KEYWORDS:

antidepressant; cortical EEG; hydroxynorketamine; ketamine; mGlu2 receptor

PMID:
30867285
PMCID:
PMC6442605
[Available on 2019-09-26]
DOI:
10.1073/pnas.1819540116

Conflict of interest statement

Conflict of interest statement: P.Z., P.J.M., C.J.T., R.M., C.A.Z., and T.D.G. are listed as coauthors in patent applications related to the pharmacology and use of (2R,6R)-HNK in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. R.M. and C.A.Z. are listed as coinventors on a patent for the use of ketamine in major depression and suicidal ideation. T.D.G. has received research funding from Janssen, Allergan, and Roche Pharmaceuticals and was a consultant for FSV7 LLC during the preceding 3 years. All of the other authors report no conflict of interest.

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