Melanocortin 3 Receptor Signaling in Midbrain Dopamine Neurons Increases the Motivation for Food Reward

The central melanocortin (MC) system mediates its effects on food intake via MC3 (MC3R) and MC4 receptors (MC4R). Although the role of MC4R in meal size determination, satiation, food preference, and motivation is well established, the involvement of MC3R in the modulation of food intake has been less explored. Here, we investigated the role of MC3R on the incentive motivation for food, which is a crucial component of feeding behavior. Dopaminergic neurons within the ventral tegmental area (VTA) have a crucial role in the motivation for food. We here report that MC3Rs are expressed on VTA dopaminergic neurons and that pro-opiomelanocortinergic (POMC) neurons in the arcuate nucleus of the hypothalamus (Arc) innervate these VTA dopaminergic neurons. Our findings show that intracerebroventricular or intra-VTA infusion of the selective MC3R agonist gamma MSH increases responding for sucrose under a progressive ratio schedule of reinforcement, but not free sucrose consumption in rats. Furthermore, ex vivo electrophysiological recordings show increased VTA dopaminergic neuronal activity upon gamma MSH application. Consistent with a dopamine-mediated effect of gamma MSH, the increased motivation for sucrose after intra-VTA infusion of gamma MSH was blocked by pretreatment with the dopamine receptor antagonist alpha-flupenthixol. Taken together, we demonstrate an Arc POMC projection onto VTA dopaminergic neurons that modulates motivation for palatable food via activation of MC3R signaling.