title: Alpha-melanocyte stimulating hormone modulates ethanol self-administration in posterior ventral tegmental area through melanocortin-4 receptors.
abstract: 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 (∼18-20 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.
authors.affiliation: Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra, India.
authors.forename: Gajanan P
authors.initials: GP
authors.lastname: Shelkar
authors.forename: Atmaram D
authors.initials: AD
authors.lastname: Kale
authors.forename: Uday
authors.initials: U
authors.lastname: Singh
authors.forename: Praful S
authors.initials: PS
authors.lastname: Singru
authors.forename: Nishikant K
authors.initials: NK
authors.lastname: Subhedar
authors.forename: Dadasaheb M
authors.initials: DM
authors.lastname: Kokare
mesh_terms: D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage* / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000378:metabolism; D058999:Drug-Seeking Behavior; D000431:Ethanol / Q000008:administration & dosage* / Q000494:pharmacology; D007031:Hypothalamus / Q000378:metabolism; D007150:Immunohistochemistry; D053486:Melanocortins / Q000819:agonists; D008845:Microinjections; D009714:Nucleus Accumbens / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012646:Self Administration; D012686:Septal Nuclei / Q000378:metabolism; D017557:Ventral Tegmental Area; D000521:alpha-MSH / Q000187:drug effects / Q000378:metabolism*
chemical_list: D002492:Central Nervous System Depressants; C116941:HS014 cyclic peptide; D053486:Melanocortins; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D000431:Ethanol; D000521:alpha-MSH
keywords: ethanol; melanocortin-4 receptors; operant chamber; reward; α-MSH