Mechanisms mediating NG-nitro- l-arginine methyl ester-induced hypophagia in mice

Abstract

N G-Nitro- l-arginine methyl ester (50 mg/kg s.c.), an inhibitor of nitric oxide (NO) synthase, has been reported to increase brain serotonin (5-hydroxytryptamine, 5-HT) metabolism and induce hypophagia. Conversely, enhanced NO synthase activity is found to be accompanied by a decrease in 5-HT level. This negative correlation between NO and 5-HT in the regulation of food intake was further studied in mice. 5-HT depletion by p-chlorophenylalanine (250 mg/kg i.p., twice daily for 2 days) failed to antagonize the hypophagic effect of N G-nitro- l-arginine methyl ester. Similarly, treatment with the NO synthesis precursor, l-arginine (1000 mg/kg s.c.), did not reverse the anorexia induced by fenfluramine (10 mg/kg s.c.), a 5-HT releaser/uptake inhibitor. Pretreatment with (-)-pindolol, methysergide and ritanserin had no effect on the hypophagic action of N G-nitro- l-arginine methyl ester, suggesting the lack of involvement of 5-HT 1 and 5-HT 2 receptors. The selective neuronal NO synthase inhibitor, 7-nitroindazole (12.5–50.0 mg/kg i.p.), however, did not exhibit any hypophagic effect whilst N G-nitro- l-arginine methyl ester increased gastric retention, which may subsequently induce satiety. Moreover, the hypophagic effect of N G-nitro- l-arginine methyl ester, which was unassociated with changes in water intake and malaise induction, was also unattenuated by cholecystokinin (CCK) receptor antagonists, devazepide (10 mg/kg i.p.) and PD 135,158 ([1 S-[1α,2β[ S∗( S∗)],4α]]-4-[[2-[[3-(1 H-indol-3-myl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl] acid N-methyl- d-glucamine salt; 1 mg/kg i.p.). Furthermore, a decrease in exploratory activity and diminished preference for favorable sensory cues were observed in N G-nitro- l-arginine methyl ester-treated animals. These results suggest that mechanisms other than 5-HT are possibly involved in mediating the hypophagic effect of N G-nitro- l-arginine methyl ester treatment in mice.