(2R,6R)-hydroxynorketamine exerts mGlu2 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 (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.


Zanos, Panos; Highland, Jaclyn N; Stewart, Brent W; Georgiou, Polymnia; Jenne, Carleigh E; Lovett, Jacqueline; Morris, Patrick; Thomas, Craig; Moaddel, Ruin; Zarate, Carlos A; Gould, Todd D;


  • Amino Acids/ antagonists & inhibitors
  • Animals
  • Antidepressive Agents/ pharmacology
  • Behavior, Animal/ drug effects
  • Bridged Bicyclo Compounds, Heterocyclic/ antagonists & inhibitors
  • Depression/ drug therapy
  • Disease Models, Animal
  • Drug Resistance
  • Female
  • Fever
  • Ketamine/ administration & dosage
  • Ketamine/ chemistry
  • Ketamine/ pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Metabotropic Glutamate/ drug effects
  • Receptors, Metabotropic Glutamate/ genetics
  • Receptors, Metabotropic Glutamate/ metabolism
  • Receptors, N-Methyl-D-Aspartate/ drug effects

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