INHIBITION OF NEURONAL NITRIC-OXIDE SYNTHASE (N-CNOS) REVERSES THE CORTICOTROPIN-INDUCED BEHAVIORAL-EFFECTS IN RATS

The nitric oxide (NO) synthase inhibitor N-G-monomethyl-L-arginine (N- NMMA) and the competitive substrate for NO synthase L-arginine were us ed to determine the role of endogenous NO on the behavioral and neuroe ndocrine responsiveness following systemic corticotrophin in dexametha sone-suppressed rats. Corticotrophin (50-200 mU/kg, s.c.) dose-depende ntly decreased behavioral activity in the actimeter and produced signi ficant anxiolytic and anti-risk activity in the plus-maze behavior tes t, without affecting systolic blood pressure. Rats given corticotrophi n showed significant increased plasma corticosterone and reduced adren al ascorbic acid level. These behavioral and adrenal responses of cort icotrophin were dose dependently blocked by metyrapone (20 and 50 mg/k g, i.p.), an inhibitor of steroid 11 beta-hydroxylase in adrenal and n eural tissues that block steroidogenesis. Intracerebroventricular admi nistration of L-NMMA (20 mu g/rat in 10 mu l) significantly prevented the behavioral hypoactivity and anxiolytic-like responses of corticotr ophin without influencing the adrenal responsiveness. The effect of L- NMMA was completely reversed by preadministration of L-arginine (300 m g/kg, i.p.). These results suggest that neuronal nitric oxide pathway plays an important modulating role in the behavioral effects of cortic otrophin by mechanisms other than those involving cardiovascular effec ts.