Antidepressant-relevant concentrations of the ketamine metabolite (2 R ,6 R )-hydroxynorketamine do not block NMDA receptor function

Significance Standard antidepressant treatments require weeks to show effectiveness. A single subanesthetic dose of ketamine rapidly attenuates many clinical signs and symptoms of depression; however, ketamine treatment also has many adverse effects, including dissociation and potential for abuse, which are mediated by NMDA glutamate receptor (NMDAR) inhibition. Previous work has revealed that the ketamine metabolite (2 R ,6 R )-hydroxynorketamine (HNK) induces antidepressant-like responses in rodents while minimizing the adverse effects observed with ketamine. The results of this study, using a multitude of experimental approaches, confirm that antidepressant-relevant concentrations of (2 R ,6 R )-HNK are not sufficient to block NMDARs. This provides a basis for work directed at alternative molecular targets and toward novel drugs that exert rapid antidepressant effects independent of NMDAR inhibition and NMDAR-mediated adverse effects.