The rapid-acting and long-lasting antidepressant effects of ()-ketamine have recently gained much attention. Although ()-ketamine has been studied as an active isomer, recent evidence suggests that ()-ketamine exhibits longer-lasting antidepressant effects than ()-ketamine in rodents. However, the antidepressant potential of ()-ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of ()-ketamine with those of ()-ketamine in animal models of depression, including a model that is refractory to current medications. Both ()-ketamine and ()-ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, ()-ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of ()-ketamine was no longer observed. Moreover, ()-ketamine, but not ()-ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by an -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both ()-ketamine and ()-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 hours). The present results confirmed the previous findings that ()-ketamine exerted longer-lasting antidepressant effects than ()-ketamine in animal models of depression. Moreover, our study is the first to demonstrate that ()-ketamine exerted a sustained antidepressant effect even in a model that is refractory to currently prescribed antidepressants.

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