Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation

Lourdes Valencia-Torres, Cristian M Olarte-Sánchez, David J Lyons, Teodora Georgescu, Megan Greenwald-Yarnell, Martin G Myers, Christopher M Bradshaw, Lora K Heisler

Research output: Contribution to journalArticlepeer-review


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-HT2CR) is a target for the treatment of human obesity. Mechanistically, 5-HT2CRs 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-HT2CRs in incentive motivation using a mathematical model of progressive ratio (PR) responding in mice. We found that the 5-HT2CR agonist lorcaserin significantly reduced both ad libitum chow intake and PR responding for chocolate pellets and increased c-fos expression in VTA 5-HT2CR expressing γ-aminobutyric acid (GABA) neurons, but not 5-HT2CR expressing dopamine (DA) neurons. We next adopted a chemogenetic approach using a 5-HT2CRCRE line to clarify the function of subset of 5-HT2C receptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT2C 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-HT2C receptor expressing neurons had no effect on the feeding behavior. These results indicate that activation of the subpopulation of 5-HT2CR 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.

Original languageEnglish
Pages (from-to)1511-1521
Number of pages11
JournalNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
Issue number7
Publication statusPublished - 1 Jun 2017


  • Animals
  • Benzazepines/pharmacology
  • Conditioning, Operant/drug effects
  • Eating/drug effects
  • Female
  • Male
  • Mice
  • Mice, Transgenic
  • Motivation/drug effects
  • Receptor, Serotonin, 5-HT2C/metabolism
  • Serotonin 5-HT2 Receptor Agonists/pharmacology
  • Ventral Tegmental Area/drug effects


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