The Role of the Melanocortin System in Linking Energy Homeostasis with Reward Mechanisms

Abstract: There is evidence of a link between peripheral signals of energy homeostasis and reward mechanisms. A hypothesis was formulated that the melanocortin (MC) system is part of this link. The hypothesis was tested by a series of receptor expression and neurochemical studies in rats.A novel autoradiographical method was developed for quantification of MC3 and MC4 receptors in the rat brain. MC receptor levels were studied in three rat models combining underweight with an increased susceptibility for alcohol and drug consumption: alcohol preferring AA rats, nandrolone treated rats and food restricted rats. The results showed that MC receptors were differentially regulated in different brain regions in the three models. Interestingly, in all models the MC3 receptor was down-regulated in the nucleus accumbens (ACB), a region involved in the reward system, thus possibly linking the MC3 receptor to reward mechanisms.In vivo microdialysis indicated that the MC peptide ?-MSH stimulates transmission of dopamine (DA), an important mediator of reward, in the ACB via an MC receptor mediated mechanism. Moreover, chronic treatment with an MC receptor agonist resulted in increased dopamine D2 receptor levels in the VTA and decreased D1 receptor levels in the ACB. The results show that melanocortins may have an important role for both acute and long term regulation of DA transmission.These results support the hypothesis that the melanocortins may serve as an important link between reward and body weight homeostasis. The results add to the understanding of the frequent co-morbidity of eating disorders and substance abuse, and the similarities between eating disorders and addiction. The more detailed understanding of the relationship between metabolic status and reward may also generate novel possibilities to treat eating disorders as well as addictive conditions.