Loss of the sustained antidepressant effect of (2R,6R)-hydroxynorketamine in NMDA receptor GluN2D subunit knockout mice

Background: The NMDA receptor antagonist ketamine exhibits acute and sustained antidepressant effects and is rapidly metabolized. We have reported that GluN2D plays an important role in the sustained antidepressant effect of (R)-ketamine, an optical isomer of ketamine. Meanwhile, the pharmacological mechanism of major metabolites of ketamine, (2R,6R;2S,6S)-hydroxynorketamine (HNK), is still unclear. In this study, we investigated the role of GluN2D in the antidepressant effect of (2R,6R;2S,6S)-HNK.