Role of NMDA receptor GluN2D subunit in the antidepressant effects and the cognitive impairment effects of enantiomers of ketamine

Soichiro Ide, Yuiko Ikekubo, Masayoshi Mishina, Kenji Hashimoto, Kazutaka Ikeda
2018 Proceedings for Annual Meeting of The Japanese Pharmacological Society  
The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine exerts rapid and sustained antidepressant effects in depressed patients. Ketamine is a racemic mixture of equal amounts of enantiomers, (R)-ketamine and (S)ketamine. The neural mechanisms that underlie different effects of these enantiomers remain unclear. We previously reported that phencyclidine, an NMDA receptor antagonist that is similar to ketamine, significantly increased locomotor activity, caused motor impairment, and
more » ... rment, and increased extracellular dopamine levels in wildtype but not GluN2D, one of NMDA receptor subunits, knockout (KO) mice. Further, GluN2D-KO mice did not develop ketamineinduced locomotor sensitization. However, roles of GluN2D in the antidepressant effects and the cognitive impairment effects of ketamine are still unknown. The present study investigated the role of GluN2D in the effects of ketamine and its enantiomers. Methods: We investigated the rapid and sustained antidepressant effects of enantiomers of ketamine (10 mg/kg) in GluN2D-KO mice using 15 min tail-suspension test (TST). The cognitive impairment effects of enantiomers of ketamine (20 mg/kg) were also investigated using novel object recognition test (NORT). In the NORT, ketamine or its enantiomers were administered just after the 10 min familiarization session, and then the 10 min test session were conducted at 24 h after the administration. Results: Intraperitoneal administration of ketamine or its enantiomers 10 min before the TST exerted significant antidepressant effects on restraint stress-induced depression in both wildtype and GluN2D-KO mice. The antidepressant effects of (RS)-ketamine and (S)-ketamine were sustained 96 h after the injection in both wildtype and GluN2D-KO mice, whereas such sustained antidepressant effects of (R)-ketamine were only observed in wildtype mice. In the NORT, the cognitive impairment effects of (RS)-ketamine and (S)-ketamine were observed in both wildtype and GluN2D-KO mice, whereas such cognitive impairment effects of (R)-ketamine were only observed in wildtype mice. Conclusions: The present results suggest that GluN2D plays an important role in the sustained antidepressant effects and the cognitive impairment effects but not rapid antidepressant effects of (R)-ketamine, whereas this submit does not appear to be involved in the antidepressant effects and the cognitive impairment effects of (RS)-ketamine or (S)ketamine.
doi:10.1254/jpssuppl.wcp2018.0_po3-1-15 fatcat:m5mnzwmvxneffcr6257q6rnxka