We previously reported that streptozotocin (STZ)-induced diabetic mice showed the depressive-like behavior in the tail suspension test. It has also been reported that leptin-deficient obese mice demonstrate the depressive-like behavior. Since STZ-induced diabetes causes a marked decrease in plasma leptin levels, it is possible that decrease in leptin levels and the depressive-like behavior may somehow be related. Therefore, we examined the effect of leptin on the depressive-like behavior of STZ-induced diabetic mice in the tail suspension test. The prolonged duration of immobility in diabetic mice was dose-dependently and significantly suppressed by single treatment with leptin (0.1-1 mg/kg, i.p.) without affecting on the locomotor activity. Leptin did not affect either the duration of immobility or the locomotor activity in non-diabetic mice. The anti-immobility effect of leptin (1 mg/kg, i.p.) in diabetic mice was significantly antagonized by the selective serotonin2 (5-HT2) receptor antagonist LY53,857 (0.03 mg/kg, s.c.), but not by the selective 5-HT1A receptor antagonist WAY-100635 (0.03 mg/kg, s.c.). Antagonists administered alone did not affect either the duration of immobility or the locomotor activity in diabetic mice. In conclusion, we suggest that leptin exerts the antidepressant-like effect in diabetic mice mediated by, at least in part, 5-HT2 receptors.