TY - JOUR T1 - Antidepressant potential of (R)-ketamine in rodent models: Comparison with (S)-ketamine JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.116.239228 SP - jpet.116.239228 AU - Kenichi Fukumoto AU - Hidetoh Toki AU - Michihiko Iijima AU - Takashi Hashihayata AU - Jun-ichi Yamaguchi AU - Kenji Hashimoto AU - Shigeyuki Chaki Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/early/2017/01/23/jpet.116.239228.abstract N2 - The rapid-acting and long-lasting antidepressant effects of (R,S)-ketamine have recently gained much attention. Although (S)-ketamine has been studied as an active isomer, recent evidence has suggested that (R)-ketamine exhibits longer-lasting antidepressant effects than (S)-ketamine in rodents. However, the antidepressant potential of (R)-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of (R)-ketamine with those of (S)-ketamine in animal models of depression, including a model that is refractory to current medications. Both (R)-ketamine and (S)-ketamine exhibited antidepressant effects at 30 min as well as at 24 h after administration in forced swimming and tail suspension tests in mice. At 48 h after administration, however, (R)-ketamine still exerted a significant antidepressant effect in the tail suspension test, while the effect of (S)-ketamine was no longer observed. Moreover, (R)-ketamine, but not (S)-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 h after a single administration. This effect was attenuated by an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both (R)-ketamine and (S)-ketamine exhibited practically the same exposure levels in plasma, brain and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (<4-8 h). The present results confirmed the previous findings that (R)-ketamine exerted longer-lasting antidepressant effects than (S)-ketamine in animal models of depression. Moreover, we demonstrated, for the first time, that (R)-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants. ER -