RESUMEN
Although the role of alpha-melanocyte stimulating hormone (α-MSH) in alcohol seeking behaviour in rats has been demonstrated, the underlying mechanisms are not understood. Herein, we test the hypothesis that α-MSH might have a permissive effect in promoting the reward action of ethanol. Rats were implanted with cannulae targeted at the posterior ventral tegmental area (pVTA), because the site is sensitive to reinforcing effects of ethanol. These rats were trained to self-administer ethanol in standard two-lever (active/inactive) operant chamber test. Each active lever press resulted in self-administration of 100 nl of ethanol (100-300 mg%) containing solution. Over a period of 7 days, ethanol significantly increased the number of lever presses, which was considered as a measure of reward. Because ethanol at 200 mg% resulted in maximum number of lever presses (â¼18-20 lever presses/30-minute session), the dose was employed in further studies. While prior administration of melanocortin (MC) agonists, α-MSH or [Nle4,D-Phe7]-alpha-MSH into pVTA, resulted in an 89% increase in lever presses, the response was attenuated following pre-treatment with MC4 receptors (MC4R) antagonist, HS014. In an immunohistochemical study, the brains of rats that were trained to self-infuse ethanol showed significantly increased α-MSH immunoreactivity in the nucleus accumbens shell, bed nucleus of stria terminalis and arcuate nucleus of the hypothalamus. In the pVTA, α-MSH fibres were found to run close to the dopamine cells, labelled with tyrosine hydroxylase antibodies. We suggest that α-MSH-MC4R system in the pVTA might be a part of the neuroadaptive mechanism underlying ethanol addiction.
Asunto(s)
Alcoholismo/metabolismo , Depresores del Sistema Nervioso Central/administración & dosificación , Etanol/administración & dosificación , Receptor de Melanocortina Tipo 4/metabolismo , Refuerzo en Psicología , Área Tegmental Ventral , alfa-MSH/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Neuronas Dopaminérgicas/metabolismo , Comportamiento de Búsqueda de Drogas , Etanol/farmacología , Hipotálamo/metabolismo , Inmunohistoquímica , Melanocortinas/agonistas , Microinyecciones , Núcleo Accumbens/metabolismo , Péptidos Cíclicos/farmacología , Ratas , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Autoadministración , Núcleos Septales/metabolismo , alfa-MSH/efectos de los fármacosRESUMEN
C-type natriuretic peptide (CNP) and its receptor are abundantly distributed in the brain, especially in the arcuate nucleus (ARC) of the hypothalamus associated with regulating energy homeostasis. To elucidate the possible involvement of CNP in energy regulation, we examined the effects of intracerebroventricular administration of CNP on food intake in mice. The intracerebroventricular administration of CNP-22 and CNP-53 significantly suppressed food intake on 4-h refeeding after 48-h fasting. Next, intracerebroventricular administration of CNP-22 and CNP-53 significantly decreased nocturnal food intake. The increment of food intake induced by neuropeptide Y and ghrelin was markedly suppressed by intracerebroventricular administration of CNP-22 and CNP-53. When SHU9119, an antagonist for melanocortin-3 and melanocortin-4 receptors, was coadministered with CNP-53, the suppressive effect of CNP-53 on refeeding after 48-h fasting was significantly attenuated by SHU9119. Immunohistochemical analysis revealed that intracerebroventricular administration of CNP-53 markedly increased the number of c-Fos-positive cells in the ARC, paraventricular nucleus, dorsomedial hypothalamus, ventromedial hypothalamic nucleus, and lateral hypothalamus. In particular, c-Fos-positive cells in the ARC after intracerebroventricular administration of CNP-53 were coexpressed with α-melanocyte-stimulating hormone immunoreactivity. These results indicated that intracerebroventricular administration of CNP induces an anorexigenic action, in part, via activation of the melanocortin system.