Methylamine-dependent release of nitric oxide and dopamine in the CNS modulates food intake in fasting rats

Abstract

Background and purpose: Methylamine is an endogenous aliphatic amine exhibiting anorexigenic properties in mice. The aim of this work was to show whether methylamine also modifies feeding behaviour in rats and, if so, to identify the mediator(s) responsible for such effects. Experimental approach: Microdialysis experiments with the probe inserted in the periventricular hypothalamic nucleus were carried out in 12 h starved, freely moving rats. Collected perfusate samples following methylamine injection (i.c.v.) were analysed for nitric oxide by chemiluminescence and for dopamine and 5-hydroxytryptamine content by HPLC. Kv1.6 potassium channel expression was reduced by antisense strategy and this decrease quantified by semi-quantitative RT-PCR analysis. Key results: Methylamine showed biphasic dose-related effects on rat feeding. At doses of 15-30 μg per rat, it was hyperphagic whereas higher doses (60-80 μg) were hypophagic. Methylamine stimulated central nitric oxide (+115% vs. basal) following hyperphagic and dopamine release (60% over basal values) at hypophagic doses, respectively. Treatment with L-N G-nitro-L-arginine-methyl ester (i.c.v. 2 μg 10 μl -1) or with α-methyl-p-tyrosine (i.p. 100 mg kg -1) before methylamine injection, reduced nitric oxide output and hyperphagia, or dopamine release and hypophagia respectively. Moreover, hypophagia and hyperphagia, as well as nitric oxide and dopamine release were significantly reduced by down-regulating brain Kv1.6 potassium channel expression. Conclusions and implications: The effects of methylamine on feeding depend on the hypothalamic release of nitric oxide and dopamine as a result of interaction at the Kv1.6 channels. The study of methylamine levels in the CNS may provide new perspectives on the physio-pathogy of alimentary behaviour. © 2007 Nature Publishing Group All rights reserved.