Activation of Ventral Tegmental Area 5-HT2C 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-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.

Selective effects of 5-HT2C receptor modulation on performance of a novel valence-probe visual discrimination task and probabilistic reversal learning in mice

“…The precise function is likely to depend on other factors including anatomical location and RNA edited state (Dracheva et al 2009 ; Lyddon et al 2013 ; Valencia-Torres et al 2017 ). For instance, previous studies indicate that 5-HT2CRs in the orbitofrontal cortex (Boulougouris and Robbins 2010 ; Alsiö et al 2015 ), dorsal raphé nucleus (Spoida et al 2014 ) and ventral tegmental area (Valencia-Torres et al 2017 ) are likely to support highly diverse behavioural functions. Therefore, studies that seek to establish putative novel antidepressants that target 5-HT2CRs should consider carefully the mixed effect on depressive symptoms that drugs of this class are likely to evoke.…”

“…Despite evidence linking 5-HT with reactivity to positive and negative feedback (Rygula et al 2015a ), the mechanisms governing the influence of this neurotransmitter on this domain are not fully established. Serotonin 2C receptors (5-HT2CRs) are associated with multiple forms of feedback-dependent behaviour, including reversal learning, motivation and food intake (Boulougouris et al 2008 ; Alsiö et al 2015 ; Bailey et al 2016 ; Xu et al 2017 ; Valencia-Torres et al 2017 ). Abnormalities in 5-HT2CR expression, activity and adenosine-to-inosine RNA editing have been linked with both depressive symptomology and the mechanisms of common antidepressant pharmacological interventions (Graeff et al 1996 ; Pälvimäki et al 1996 ; Martin et al 2014 ).…”

Serotonin in Animal Cognition and Behavior

“…However, due to its toxic effects on the heart, d-fenfluramine has been withdrawn from the market, and it has been replaced by the 5-HT 2C R agonist lorcaserin [125]. The multiplicity of mechanisms by which 5-HT modulates feeding behavior is attested by the variety of 5-HTRs implicated (5-HT 1A R, 5-HT 1B R, 5-HT 2C R, 5-HT 4 R), and by the diversity of the brain areas involved in this behavior, for example sub-regions of the hypothalamus [126], the ventral tegmental area, or the nucleus of the solitary tract [127,128]. 5-HT would inhibit feeding behavior via reinforcement of satiety signals and the extension of their duration, likely via a diversity of 5-HT receptors.…”

Neuropharmacology of compulsive eating

“…One potential mechanism for 5-HT drugs to reduce binge eating was found to be through 5-HT2c receptor activation of dopamine neurons in the ventral tegmental area (VTA) [112]. The obesity medication lorcaserin (a 5HT-2c selective agonist) has been shown to reduce both homeostatic feeding as well as the incentive value of food through VTA 5-HT2c activation [113]. d-Amphetamine, which inhibits monoamine reuptake, including serotonin, has been shown to increase 5-HT concentrations in the striatum [114].…”