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


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.

SUBMITTER: Zanos P 

PROVIDER: S-EPMC6442605 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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(<i>2R,6R</i>)-hydroxynorketamine exerts mGlu<sub>2</sub> receptor-dependent antidepressant actions.

Zanos Panos P   Highland Jaclyn N JN   Stewart Brent W BW   Georgiou Polymnia P   Jenne Carleigh E CE   Lovett Jacqueline J   Morris Patrick J PJ   Thomas Craig J CJ   Moaddel Ruin R   Zarate Carlos A CA   Gould Todd D TD  

Proceedings of the National Academy of Sciences of the United States of America 20190313 13


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 (<i>2R</i>,<i>6R</i>)-hydroxynorketamine [(<i>2R</i>,<i>6R</i>)-HNK] is a rapid-acting antidepressant drug candidate with limited dissociation properties and abuse potential. We as  ...[more]

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