Furthermore, SB216763 attenuated cocaine-induced hyperactivity, but only partially attenuated hyperactivity produced by SKF-82958. These results suggest that systemic administration of SB216763 could inhibit GSK-3 in the brain. However, we could find no BAY 299 antidepressant effect for SB216763 in the mouse CMS model and control mice, although the dose used in this study could cause GSK-3 inhibition in the brain. A recent study showed that intracerebroventricular injection of SB216763 attenuated behavioral abnormalities in mice that had been administered ketamine, suggesting that SB216763 is capable of blocking the effects of ketamine in mice. Taken together, it is unlikely that a direct inhibition of GSK-3 is involved in the rapid antidepressant action of ketamine in the CMS mouse model, although a further study using lower doses is needed. Previous reports showed that the selective, brain-permeable GSK-3 inhibitor, AR-A014418, decreased FST immobility time in control rats. However, treatment with AR-A014418 DIM-C-pPhOH resulted in a spontaneous and generalized reduction in locomotor activity in mice, indicating that this induced reduction in activity constitutes its therapeutic action. The effects of ARA014418 were detectable as early as 30 minutes after a single dosing, although behavioral tests were not performed until 24 hours after dosing. In this study, we found no antidepressant effect for ketamine or SB216763 in control mice, at the 30 minute time point, after a single dosing, in contrast with previous reports. The reasons for this discrepancy are currently unclear. However, we found that ketamine, but not SB21673, showed antidepressant activity in control mice 24 hours after a single administration, suggesting that ketamine induces longlasting antidepressant effects in control mice. In this study, no acute experiments using SB216763 in the CMS model were performed within the earlier time frame, after a single dosing. Therefore, it would be interesting to examine the earlier time effects of ketamine and SB216763 in the CMS model. It would also be intriguing to examine whether chronic administration of SB216763 exerts an antidepressant effect in the CMS model. As mentioned previously, the effects of ketamine were detectable from 24 hours to 8 days after a single dosing, even though ketamine would no longer be present in the body, due to rapid clearance. Although this possibility was raised by Beurel et al., we could find no evidence of an antidepressant-like effect for SB216763 in the CMS mouse model and control mice. It was reported that ketamine increases the phosphorylation of GSK- 3, and that mice with a knock-in mutation that blocks this phosphorylation, do not respond to ketamine in a depression model. In addition, it has been shown that the NMDA receptor antagonists, such as phencyclidine and dizocilpine, transiently could increase GSK-3b activity and increase the active forms of GSK-3b and decrease the inactive forms in the rat forebrain. Further detailed studies are therefore, required to determine the mechanisms underlying the induction of GSK-3 phosphorylation by ketamine.