Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis

Leptin administration inhibits diencephalic nitric oxide synthase (NOS) act ivity and increases brain serotonin (5-HT) metabolism in mice. We evaluated food intake, body-weight gain, diencephalic NOS activity, and diencephalic content of tryptophan (TRP), 5-HT, hydroxyindoleacetic acid (5-HIAA), and 5-HIAA/5-HT ratio after intracerebroventricular (ICV) or intraperitoneal (I P) leptin injection in mice. Five consecutive days of ICV or IP leptin inje ctions induced a significant reduction in neuronal NOS (nNOS) activity, and caused a dose-dependent increase of 5-HT, 5-HIAA, and the 5-HIAA/5-HT rati o. Diencephalic 5-HT metabolism showed a significant increase in 5-HT, 5-HI AA, and the 5HIAA/5-HT ratio 3 hours after a single leptin injection. This effect was maintained for 3 hours and had disappeared by 12 hours after inj ection. After a single IP leptin injection, the peak for 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio was achieved at 6 hours. Single injections of ICV or IP leptin significantly increased diencephalic 5-HT content. Leptin-induced 5-HT increase was antagonized by the coadministration of L-arginine only w hen the latter was ICV injected, whereas D-arginine did not influence lepti n effects on brain 5-HT content. Finally, in nNOS-knockout mice, the appeti te-suppressant activity of leptin was strongly reduced, and the leptin-indu ced increase in brain 5-HT metabolism was completely abolished. Our results indicate that the L-arginine/NO pathway is involved in mediating leptin ef fects on feeding behavior, and demonstrate that nNOS activity is required f or the effects of leptin on brain 5-HT turnover.