Activation of Ventral Tegmental Area 5-HT2C 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-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.

[1]  C. Bradshaw,et al.  Effects of SKF-83566 and haloperidol on performance on progressive ratio schedules maintained by sucrose and corn oil reinforcement: quantitative analysis using a new model derived from the Mathematical Principles of Reinforcement (MPR) , 2013, Psychopharmacology.

[2]  M. Low,et al.  Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons , 2016, Molecular metabolism.

[3]  M. Low,et al.  Activation of Central Melanocortin Pathways by Fenfluramine , 2002, Science.

[4]  Brian M. Smith,et al.  Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine2C Agonist: in Vitro and in Vivo Pharmacological Characterization , 2008, Journal of Pharmacology and Experimental Therapeutics.

[5]  L. Cervo,et al.  Stimulation of serotonin2C receptors influences cocaine-seeking behavior in response to drug-associated stimuli in rats , 2008, Psychopharmacology.

[6]  J. Salamone,et al.  Dopamine and Food Addiction: Lexicon Badly Needed , 2013, Biological Psychiatry.

[7]  W HODOS,et al.  Progressive Ratio as a Measure of Reward Strength , 1961, Science.

[8]  E. Szabadi,et al.  A clozapine-like effect of cyproheptadine on progressive ratio schedule performance , 2012, Journal of psychopharmacology.

[9]  Kevin W. Williams,et al.  5-HT2CRs Expressed by Pro-Opiomelanocortin Neurons Regulate Energy Homeostasis , 2008, Neuron.

[10]  U. Spampinato,et al.  Pharmacological and genetic interventions in serotonin (5-HT)2C receptors to alter drug abuse and dependence processes , 2012, Brain Research.

[11]  P. Fletcher,et al.  The 5-HT2C receptor agonist lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity , 2016, Neuropharmacology.

[12]  J. Staddon,et al.  Dynamics of waiting in pigeons. , 1996, Journal of the experimental analysis of behavior.

[13]  E. Levin,et al.  Lorcaserin, a 5-HT2C Agonist, Decreases Nicotine Self-Administration in Female Rats , 2011, Journal of Pharmacology and Experimental Therapeutics.

[14]  K. Cunningham,et al.  5-HT2C Receptors Localize to Dopamine and GABA Neurons in the Rat Mesoaccumbens Pathway , 2011, PloS one.

[15]  C. Bradshaw,et al.  Quantitative analysis of performance on a progressive-ratio schedule: effects of reinforcer type, food deprivation and acute treatment with Δ9-tetrahydrocannabinol (THC) , 2015, Behavioural Processes.

[16]  E. Levin,et al.  Lorcaserin, a selective 5-HT2C receptor agonist, decreases alcohol intake in female alcohol preferring rats , 2014, Pharmacology Biochemistry and Behavior.

[17]  C. Bradshaw,et al.  Effect of streptozotocin-induced diabetes on performance on a progressive ratio schedule , 2014, Psychopharmacology.

[18]  P. Fletcher,et al.  Effects of the 5-HT2C receptor agonist Ro60-0175 and the 5-HT2A receptor antagonist M100907 on nicotine self-administration and reinstatement , 2012, Neuropharmacology.

[19]  G. Kranz,et al.  Reward and the serotonergic system , 2010, Neuroscience.

[20]  A. Cooper,et al.  The 5-HT2C receptor agonist, lorcaserin, and the 5-HT6 receptor antagonist, SB-742457, promote satiety; a microstructural analysis of feeding behaviour , 2015, Psychopharmacology.

[21]  M. Low,et al.  5-HT Obesity Medication Efficacy via POMC Activation is Maintained During Aging , 2014, Endocrinology.

[22]  P. Killeen,et al.  Progressive ratio schedules of reinforcement. , 2009, Journal of experimental psychology. Animal behavior processes.

[23]  J. Blundell.  Serotonin manipulations and the structure of feeding behaviour , 1986, Appetite.

[24]  Steven M. Graves,et al.  Serotonin2C receptors in the ventral pallidum regulate motor function in rats , 2013, Neuroreport.

[25]  D. Burdakov,et al.  5-HT2C Receptor Agonist Anorectic Efficacy Potentiated by 5-HT1B Receptor Agonist Coapplication: An Effect Mediated via Increased Proportion of Pro-Opiomelanocortin Neurons Activated , 2013, The Journal of Neuroscience.

[26]  K. Cunningham,et al.  Distribution of serotonin 5-HT2C receptors in the ventral tegmental area , 2007, Neuroscience.

[27]  J. Salamone,et al.  Effects of Dopamine Antagonists and Accumbens Dopamine Depletions on Time-Constrained Progressive-Ratio Performance , 1998, Pharmacology Biochemistry and Behavior.

[28]  P. Fletcher,et al.  Characterizing the effects of 5-HT2C receptor ligands on motor activity and feeding behaviour in 5-HT2C receptor knockout mice , 2009, Neuropharmacology.

[29]  L. Cervo,et al.  Stimulation of serotonin2C receptors influences cocaine-seeking behavior in response to drug-associated stimuli in rats , 2008, Psychopharmacology.

[30]  N. R. Richardson,et al.  Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy , 1996, Journal of Neuroscience Methods.

[31]  M. Nicolelis,et al.  Remote Control of Neuronal Activity in Transgenic Mice Expressing Evolved G Protein-Coupled Receptors , 2009, Neuron.

[32]  A. Greenshaw,et al.  Differential effects of 5-HT2C receptor activation by WAY 161503 on nicotine-induced place conditioning and locomotor activity in rats , 2009, Behavioural Brain Research.

[33]  P. Killeen.  Mathematical principles of reinforcement , 1994 .

[34]  P. Fletcher,et al.  The 5-HT2C Receptor Agonist Lorcaserin Reduces Nicotine Self-Administration, Discrimination, and Reinstatement: Relationship to Feeding Behavior and Impulse Control , 2012, Neuropsychopharmacology.

[35]  JaneR . Taylor,et al.  The drive to eat: comparisons and distinctions between mechanisms of food reward and drug addiction , 2012, Nature Neuroscience.

[36]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[37]  A. Hill,et al.  Sensitivity of the appetite control system in obese subjects to nutritional and serotoninergic challenges. , 1990, International journal of obesity.

[38]  E. Esposito,et al.  Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin2C receptors , 2000, Brain Research.

[39]  U. Spampinato,et al.  Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine , 2008, Neuropsychopharmacology.

[40]  B. Roth,et al.  DREADDs (designer receptors exclusively activated by designer drugs): chemogenetic tools with therapeutic utility. , 2015, Annual review of pharmacology and toxicology.

[41]  P. Killeen,et al.  A theory of behaviour on progressive ratio schedules, with applications in behavioural pharmacology , 2012, Psychopharmacology.

[42]  B. Roth,et al.  Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype-targeted drugs. , 2013, The Journal of clinical investigation.

[43]  T. Morera-Herreras,et al.  Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease , 2014, Front. Neural Circuits.

[44]  J. Woods,et al.  Effects of GBR 12909 and cocaine on cocaine-maintained behavior in rhesus monkeys. , 1993, Drug and alcohol dependence.

[45]  S. O’Rahilly,et al.  Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. , 2008, Endocrinology.

[46]  P. G. Clifton,et al.  Animal models to explore the effects of CNS drugs on food intake and energy expenditure , 2012, Neuropharmacology.

[47]  L. Heisler,et al.  5‐Hydroxytryptamine Medications for the Treatment of Obesity , 2015, Journal of neuroendocrinology.

[48]  Corby K. Martin,et al.  Lorcaserin, a 5-HT(2C) receptor agonist, reduces body weight by decreasing energy intake without influencing energy expenditure. , 2011, Journal of Clinical Endocrinology and Metabolism.

[49]  C. Bradshaw,et al.  Evidence for a role of 5-HT2C receptors in the motor aspects of performance, but not the efficacy of food reinforcers, in a progressive ratio schedule , 2014, Psychopharmacology.