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

ABSTRACT: 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.

SUBMITTER: Valencia-Torres L

PROVIDER: S-EPMC5362069 | biostudies-literature |

REPOSITORIES: biostudies-literature

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