title: Activation of Ventral Tegmental Area 5-HT2CReceptors 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-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-HT2CRCREline to clarify the function of subset of 5-HT2Creceptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT2Creceptor 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-HT2Creceptor 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.
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Valencia-Torres
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Cristian M
authors.initials: CM
authors.lastname: Olarte-Sánchez
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lyons
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Teodora
authors.initials: T
authors.lastname: Georgescu
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Greenwald-Yarnell
authors.affiliation: Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.affiliation: Division of Psychiatry, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bradshaw
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Lora K
authors.initials: LK
authors.lastname: Heisler
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004435:Eating / Q000187:drug effects / Q000502:physiology* / Q000523:psychology; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009042:Motivation / Q000187:drug effects / Q000502:physiology*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001552:Benzazepines; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; C506658:lorcaserin