REGULATING NEUROPEPTIDES IN ALCOHOL ADDICTION : FOCUS ON MELANIN CONCENTRATING HORMONE AND ITS MCH 1-RECEPTOR

Current treatment options for alcohol use disorders are limited in number and have limited efficacy. It is therefore important to find new, more effective medications. In this thesis, the work focused on the involvement of the hypothalamic neuropeptide Melanin Concentrating Hormone (MCH) and its MCH-1 receptor (MCH1-R) in alcohol related behaviors in rodents. In the initial study, the selective MCH1-R antagonist GW803430 was evaluated in animal models of motivation to obtain alcohol and relapse to alcohol-seeking in rats using operant self-administration. GW803430 potently attenuated alcohol self-administration and cueinduced reinstatement while reinstatement induced by a foot-shock stressor was unaffected. To extend these findings, GW803430 was assessed in states of escalated alcohol consumption. In rats consuming high amounts of alcohol during intermittent access GW803430 treatment significantly reduced intake of both alcohol and feed while in low drinking rats only food intake was decreased. Following protracted abstinence induced by intermittent access, alcohol self-administration was significantly attenuated by GW803430. In contrast, GW803430 had no effect on escalated alcohol self-administration induced by vapor exposure. These studies provide evidence for a combined effect of the MCH1-R antagonist on consumption of alcohol through effects both on appetite for calories, and rewarding alcohol actions. In order to evaluate effects on sugar, which also has addiction-like properties and activate pathways in the brain overlapping those for drugs of abuse, we assessed GW803430 on sucrose and saccharin self-administration. While sucrose consumption was significantly decreased by GW803430, no effect was seen on saccharin intake, suggesting that MCH1-R blockade primarily regulates calorie intake. However, GW803430 also reduced cue-induced seeking and enhanced motivation to obtain sucrose under a progressive ratio schedule. Reward from palatable food and drugs of abuse can activate overlapping neurobiological mechanisms, and the findings further indicate that the MCH1-R may have a dual role on appetite for calories and reward. Based on the findings that the MCH1-R regulates the rewarding properties of both alcohol and sucrose, alcohol reward was investigated in mice in the conditioned place preference (CPP) model to avoid calorie intake as a confounding variable. Genetic deletion of the MCH1-R prevented alcohol induced CPP and this finding was replicated in wildtype C57BL/6 mice treated with GW803430. Downstream signaling mechanisms of the MCH1-R after acute alcohol administration were further investigated. Immunohistochemistry showed that acute alcohol administration induced phosphorylation of the dopamine and cAMP regulated phospho protein 32 (p-DARPP-32) downstream of the MCH1-R. In conclusion, our results suggest a role of MCH and its MCH1-R both in calorie intake and in regulation of alcohol reward. LIST OF SCIENTIFIC PAPERS I. A. Cippitelli, C. Karlsson, J L. Shaw, A. Thorsell, D R. Gehlert and M. Heilig. Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats. Psychopharmacology 2010, 211:367-375. II. C. Karlsson, A. Asif, F A. Rehman, C. Pitcairn, R. Barchiesi, P. Steensland, D R. Gehlert, M. Heilig and A. Thorsell. Melanin-concentrating hormone and its MCH-1 receptor: Relationship between effects on alcohol and caloric intake. Manuscript. III. C. Karlsson, M. Zook, R. Ciccocioppo, D R. Gehlert, A. Thorsell, M. Heilig and A. Cippitelli. Melanin-concentrating hormone receptor 1 (MCH1-R) antagonism: Reduced appetite for calories and suppression of addictive-like behaviors. Pharmacology, Biochemistry and Behavior 2012, 102:400-406. IV. C. Karlsson, F A. Rehman, R. Damadzic, J R. Schank, D R. Gehlert, P. Steensland, A. Thorsell and M. Heilig. The melanin-concentrating hormone-1 receptor (MCH1-R) modulates alcohol-induced reward and pDARPP-32 stimulation. Manuscript. CONTENTS