Several lines of evidence have indicated that the prevalence of depression in diabetic subjects is higher than that in the general population, however, little information is available on the effects of antidepressants in diabetes. In the present study, the antidepressant-like effect mediated by the activation of 5-HT(1A) receptors was examined using the tail suspension test in streptozotocin-induced diabetic mice. Long-lasting increases in 5-HT turnover rates were observed in the diabetic mouse midbrain and frontal cortex, but not in the hippocampus. Duration of immobility was significantly longer in diabetic than in nondiabetic mice in the tail suspension test. The 5-HT(1A) receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (3-30 microg/kg, i.p.) reduced the duration of immobility in nondiabetic mice, and this effect was completely antagonized by pretreatment with N-[2-[4-(2-methoxyphenil)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) (30 microg/kg, s.c.), a selective 5-HT(1A) receptor antagonist. In contrast, 8-OH-DPAT (3 microg/kg-3 mg/kg, i.p.) was ineffective in diabetic mice. The selective 5-HT reuptake inhibitor fluoxetine (3-56 mg/kg, i.p.) reduced the duration of immobility in both nondiabetic and diabetic mice. However, fluoxetine was less effective in diabetic mice than in nondiabetic mice. WAY-100635 (30 microg/kg, s.c.) reversed the suppression of the duration of immobility by fluoxetine (30 mg/kg, i.p.) in nondiabetic mice. On the other hand, the anti-immobility effect of fluoxetine (56 mg/kg, i.p.) was not antagonized by WAY-100635 (30 microg/kg, s.c.) in diabetic mice. The selective 5-HT(2) receptor antagonist 6-methyl-1-(1-methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY53,857) (30 microg/kg, s.c.) reversed the anti-immobility effect of fluoxetine in both nondiabetic and diabetic mice. Spontaneous locomotor activity in diabetic mice was not different from that in nondiabetic mice. 8-OH-DPAT (30 microg/kg, i.p.), but not fluoxetine, increased the spontaneous locomotor activity in both nondiabetic and diabetic mice. The number of 5-HT(1A) receptors in the mouse frontal cortex was unaffected by diabetes. Plasma corticosterone levels in diabetic mice were significantly higher than that in nondiabetic mice. These results suggest that the antidepressant-like effect mediated by 5-HT(1A) receptors may be attenuated by diabetes.