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

Abstract

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 γMSH 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 γMSH application. Consistent with a dopamine-mediated effect of γMSH, the increased motivation for sucrose after intra-VTA infusion of γMSH was blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. Taken together, we demonstrate an Arc POMC projection onto VTA dopaminergic neurons that modulates motivation for palatable food via activation of MC3R signaling.

Melanocortin 4 receptor is not required for estrogenic regulations on energy homeostasis and reproduction

“…Further, it has been reported that leptin-induced anorexia is blocked in MC3R null mice, but remains intact in MC4R null mice [30], which indicates that the anorexigenic effects of leptin require the MC3R, but not the MC4R. Additionally, a recent study demonstrated that the MC3R within the ventral tegmental area regulates the incentive motivation for food, which is an essential component of feeding behavior [32]. Combined the negative observation in MC4R null mice in our study and previous reports on anorexigenic effects of the MC3R, the MC3R is likely to contribute to estrogenic regulation of food intake in female mice.…”

Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression

“…Serotonin has traditionally been the transmitter linked with depression, based on pharmacological studies of antidepressant drugs that target the serotonin system, or depletion of serotonin in the CNS 97 . However, many of the symptoms seen in depression — such as anhedonia and amotivation — have been more consistently associated with dysfunctions in the DA system 45, 98–100 . Studies have identified hyperactivity in prefrontal cortical area 25 as a correlate of depression 101 .…”

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

“…In addition, the MC3R – but not the MC4R – was recently reported to be expressed in up to a third of dopaminergic neurons of the VTA [116]. Recently, arcuate POMC neurons projecting to VTA dopaminergic neurons have been shown to modulate motivation for palatable food via MC3Rs [117]. Others have reported the MC4R is also present within the VTA [26, 118].…”