The effects of N^G-nitro-L-arginine, an inhibitor of brain nitric oxide (NO) synthase, on central serotoninergic system were studied in male obese Zucker rats and in their lean age-matched controls (FA/?; FA/FA), both groups aged 14 weeks. Acute injection of N^G-nitro-L-arginine (50 mg/kg i.p.) or repeated administration of N^G-nitro-L-arginine (50 mg/kg i.p. daily, for 7 days) reduced food intake and body weight in obese rats. Acute administration of N^G-nitro-L-arginine reduced food intake in lean rats. However, lean rats showed tolerance to the N^G-nitro-L-arginine effects after repeated administration. N^G-Nitro- L-arginine administration significantly increased serotonin metabolism in the cortex, diencephalon and medulla-pons of obese Zucker rats after either acute or repeated administration of N^G-nitro-L-arginine. In contrast, N^G-nitro-L-arginine increased serotonin metabolism in lean rats only after acute administration, and the appearance of tolerance to N^G-nitro-L-arginine anorectic effects paralleled the failure of N^G-nitro-L-arginine to increase serotonin metabolism. The present data extend our previous findings indicating that N^G-nitro-L-arginine possesses anorectic activity in obese Zucker rats, and clearly suggest that the central serotoninergic system mediates the anorexia induced by inhibitors of brain NO synthase.