Activation of Ventral Tegmental Area 5-HT_2C Receptors Reduces Incentive Motivation

Obesity is primarily due to food intake in excess of the body's energetic requirements, intake that is not only associated with hunger but also the incentive value of food. The 5-hydroxytryptamine 2C receptor (5-HT_2CR) is a target for the treatment of human obesity. Mechanistically, 5-HT_2CRs are positioned to influence both homeostatic feeding circuits within the hypothalamus and reward circuits within the ventral tegmental area (VTA). Here we investigated the role of 5-HT_2CRs in incentive motivation using a mathematical model of progressive ratio (PR) responding in mice. We found that the 5-HT_2CR agonist lorcaserin significantly reduced both ad libitum chow intake and PR responding for chocolate pellets and increased c-fos expression in VTA 5-HT_2CR expressing γ-aminobutyric acid (GABA) neurons, but not 5-HT_2CR expressing dopamine (DA) neurons. We next adopted a chemogenetic approach using a 5-HT_2CR^CRE line to clarify the function of subset of 5-HT_2C receptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT_2C receptor expressing neurons significantly reduced ad libitum chow intake, operant responding for chocolate pellets, and the incentive value of food. In contrast, chemogenetic inhibition of VTA 5-HT_2C receptor expressing neurons had no effect on the feeding behavior. These results indicate that activation of the subpopulation of 5-HT_2CR neurons within the VTA is sufficient to significantly reduce homeostatic feeding and effort-based intake of palatable food, and that this subset has an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity.