Ventral Tegmental Area Amylin Receptor Activation Differentially Modulates Mesolimbic Dopamine Signaling in Response to Fat versus Sugar

Abstract

Amylin, a pancreatic hormone that is co-secreted with insulin, has been highlighted as a potential treatment target for obesity. Amylin receptors are distributed widely throughout the brain and are co-expressed on mesolimbic dopamine neurons. Activation of amylin receptors is known to reduce food intake, but the neurochemical mechanisms behind this remain to be elucidated. Amylin receptor activation in the ventral tegmental area (VTA), a key dopaminergic nucleus in the mesolimbic reward system, has a potent ability to suppress intake of palatable fat and sugar solutions. Although previous work has demonstrated that VTA amylin receptor activation can dampen mesolimbic dopamine signaling elicited by random delivery of sucrose, whether this is also the case for fat remains unknown. Herein we tested the hypothesis that amylin receptor activation in the VTA of male rats would attenuate dopamine signaling in the nucleus accumbens core in response to random intraoral delivery of either fat or sugar solutions. Results show that fat solution produces a greater potentiation of accumbens dopamine than an isocaloric sucrose solution. Moreover, activation of VTA amylin receptors elicits a more robust suppression of accumbens dopamine signaling in response to fat solution than to sucrose. Taken together these results shed new light on the amylin system as a therapeutic target for obesity and emphasize the reinforcing nature of high-fat/high-sugar diets.Significance StatementMesolimbic amylin receptor activation has strong anorectic effects, with a more robust suppression of fat versus sucrose intake. However, the neurochemical mechanisms underlying these differential effects remain unclear. The results of these studies demonstrate that pharmacological activation of amylin receptors in the ventral tegmental area attenuates dopamine signaling in the nucleus accumbens core evoked by intraoral administration of isocaloric fat or sucrose solution, but with a greater suppression of the fat-enhanced dopamine. These findings provide a potential physiological basis for the differential amylin-mediated intake responses toward these nutrients and further highlight this system as a promising therapeutic target for obesity.