Send to

Choose Destination
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

Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201.
Program in Toxicology, University of Maryland School of Medicine, Baltimore, MD 21201.
Biomedical Research Center, National Institute on Aging, NIH, Baltimore, MD 21224.
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD 20892.
Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, MD 20892.
Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201;
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201.
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201.
Veterans Affairs Maryland Health Care System, Baltimore, MD 21201.


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.


antidepressant; cortical EEG; hydroxynorketamine; ketamine; mGlu2 receptor

[Indexed for MEDLINE]
Free PMC Article

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.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center