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.
Methods: We investigated the acute and sustained antidepressant effects of (2R,6R;2S,6S)-HNK on 4 h restraint stress-induced depression in wild-type and GluN2D-KO mice using the tail-suspension test (TST). After behavioral tests, mouse brains were removed and brain regions considered to be related to the antidepressant effect were collected and examined for protein expression of neuroplasticity-related molecules using the Western Blotting (WB).
Results: (2R,6R)-HNK, but not (2S,6S)-HNK, reduced immobility time in the TST 10 min after administration in wild-type and GluN2D-KO mice. Further, the sustained antidepressant effect at 96 h post-treatment was observed only in wild-type mice and disappeared in GluN2D-KO mice. We analyzed the changes in protein expression levels of molecules assumed to be related to neuroplasticity by the WB.
Conclusion: Among the major metabolites of ketamine, (2R,6R)-HNK has acute and sustained antidepressant effects and GluN2D plays an important role in the sustained antidepressant effects of (2R,6R)-HNK.