()-hydroxynorketamine exerts mGlu receptor-dependent antidepressant actions.

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