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

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

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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-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 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 plays 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
Volume42
Issue number7
Early online date21 Dec 2016
DOIs
Publication statusPublished - Jun 2017

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Receptor, Serotonin, 5-HT2C
Ventral Tegmental Area
Serotonin Receptors
Motivation
Neurons
Obesity
Food
Eating
Aminobutyrates
GABAergic Neurons
Hunger
Dopaminergic Neurons
Feeding Behavior
Appetite
Reward
Hypothalamus
Theoretical Models
Therapeutics

Cite this

Valencia-Torres, L., Olarte-Sanchez, C. M., Lyons, D. J., Georgescu, T., Greewald-Yarnell, M., Myers, M. G., ... Heisler, L. K. (2017). Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation. Neuropsychopharmacology, 42(7), 1511-1521. https://doi.org/10.1038/npp.2016.264

Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation. / Valencia-Torres, Lourdes; Olarte-Sanchez, Cristian M.; Lyons, David J.; Georgescu, Teodora; Greewald-Yarnell, Megan; Myers, Martin G.; Bradshaw, Christopher M.; Heisler, Lora K.

In: Neuropsychopharmacology, Vol. 42, No. 7, 06.2017, p. 1511-1521.

Research output: Contribution to journalArticle

Valencia-Torres, L, Olarte-Sanchez, CM, Lyons, DJ, Georgescu, T, Greewald-Yarnell, M, Myers, MG, Bradshaw, CM & Heisler, LK 2017, 'Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation', Neuropsychopharmacology, vol. 42, no. 7, pp. 1511-1521. https://doi.org/10.1038/npp.2016.264
Valencia-Torres L, Olarte-Sanchez CM, Lyons DJ, Georgescu T, Greewald-Yarnell M, Myers MG et al. Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation. Neuropsychopharmacology. 2017 Jun;42(7):1511-1521. https://doi.org/10.1038/npp.2016.264
Valencia-Torres, Lourdes ; Olarte-Sanchez, Cristian M. ; Lyons, David J. ; Georgescu, Teodora ; Greewald-Yarnell, Megan ; Myers, Martin G. ; Bradshaw, Christopher M. ; Heisler, Lora K. / Activation of Ventral Tegmental Area 5-HT2C Receptors Reduces Incentive Motivation. In: Neuropsychopharmacology. 2017 ; Vol. 42, No. 7. pp. 1511-1521.
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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-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 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 plays an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity.",
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note = "FUNDING AND DISCLOSURE The research was funded by Wellcome Trust (WT098012) to LKH; and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The remaining authors declare no conflict of interest. ACKNOWLEDGMENTS We thank Dr Celine Cansell, Ms Raffaella Chianese and the staff of the Medical Research Facility for technical assistance. We thank Dr Vladimir Ordu{\~n}a for the scientific advice and technical assistance.",
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AU - Valencia-Torres, Lourdes

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N1 - FUNDING AND DISCLOSURE The research was funded by Wellcome Trust (WT098012) to LKH; and National Institute of Health (DK056731) and the Marilyn H. Vincent Foundation to MGM. The University of Michigan Transgenic Core facility is partially supported by the NIH-funded University of Michigan Center for Gastrointestinal Research (DK034933). The remaining authors declare no conflict of interest. ACKNOWLEDGMENTS We thank Dr Celine Cansell, Ms Raffaella Chianese and the staff of the Medical Research Facility for technical assistance. We thank Dr Vladimir Orduña for the scientific advice and technical assistance.

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N2 - 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 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 plays an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity.

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