( <i>2R,6R</i> )-hydroxynorketamine exerts mGlu ₂ 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 (<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 assessed the role of group II metabotropic glutamate receptor subtypes 2 (mGlu₂) and 3 (mGlu₃) in the antidepressant-relevant actions of (<i>2R</i>,<i>6R</i>)-HNK using behavioral, genetic, and pharmacological approaches as well as cortical quantitative EEG (qEEG) measurements in mice. Both ketamine and (<i>2R</i>,<i>6R</i>)-HNK prevented mGlu_2/3 receptor agonist (LY379268)-induced body temperature increases in mice lacking the <i>Grm3</i>, but not <i>Grm2</i>, gene. This action was not replicated by NMDA receptor antagonists or a chemical variant of ketamine that limits metabolism to (<i>2R</i>,<i>6R</i>)-HNK. The antidepressant-relevant behavioral effects and 30- to 80-Hz qEEG oscillation (gamma-range) increases resultant from (<i>2R</i>,<i>6R</i>)-HNK administration were prevented by pretreatment with an mGlu_2/3 receptor agonist and absent in mice lacking the <i>Grm2</i>, but not <i>Grm3</i>^-/-, gene. Combined subeffective doses of the mGlu_2/3 receptor antagonist LY341495 and (<i>2R</i>,<i>6R</i>)-HNK exerted synergistic increases on gamma oscillations and antidepressant-relevant behavioral actions. These findings highlight that (<i>2R</i>,<i>6R</i>)-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 (<i>2R</i>,<i>6R</i>)-HNK and inhibitors of mGlu₂ receptor function in clinical trials for treatment-resistant depression either alone or in combination.