The 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) reduces palatable food consumption and BOLD fMRI responses to food images in healthy female volunteers

Abstract

RationaleBrain 5-HT2C receptors form part of a neural network that controls eating behaviour. 5-HT2C receptor agonists decrease food intake by activating proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus, but recent research in rodents has suggested that 5-HT2C receptor agonists may also act via dopaminergic circuitry to reduce the rewarding value of food and other reinforcers. No mechanistic studies on the effects of 5-HT2C agonists on food intake in humans have been conducted to date.ObjectivesThe present study examined the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) on food consumption, eating microstructure and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) responses to food pictures in healthy female volunteers.MethodsIn a double-blind, placebo-controlled, crossover design, participants were randomized immediately after screening to receive oral mCPP (30mg) in a single morning dose, or placebo, in a counterbalanced order. Test foods were served from a Universal Eating Monitor (UEM) that measured eating rate and fMRI BOLD signals to the sight of food and non-food images were recorded.ResultsmCPP decreased rated appetite and intake of a palatable snack eaten in the absence of hunger but had no significant effect on the consumption of a pasta lunch (although pasta eating rate was reduced). mCPP also decreased BOLD fMRI responses to the sight of food pictures in areas of reward-associated circuitry. A post hoc analysis identified individual variability in the response to mCPP (exploratory responder-non-responder analysis). Some participants did not reduce their cookie intake after treatment with mCPP and this lack of response was associated with enhanced ratings of cookie pleasantness and enhanced baseline BOLD responses to food images in key reward and appetite circuitry.ConclusionsThese results suggest that 5-HT2C receptor activation in humans inhibits food reward-related responding and that further investigation of stratification of responding to mCPP and other 5-HT2C receptor agonists is warranted.Electronic supplementary materialThe online version of this article (10.1007/s00213-017-4764-9) contains supplementary material, which is available to authorized users.

Role of impulsivity and reward in the anti-obesity actions of 5-HT2C receptor agonists

“…The results of a recent study by Thomas et al (2017) are consistent with those reported by Farr et al (2016). These authors found that in healthy female volunteers, the non-selective 5-HT 2C agonist mCPP reduced the consumption of a palatable cookie snack, but not a pasta lunch consumed in a hungry state.…”

“…Concurrent fMRI showed that mCPP attenuated the food cue-induced increase in BOLD activity in multiple brain regions including dorsolateral prefrontal cortex, cingulate cortex and insula. Similar to Farr and coworkers, Thomas et al (2017) propose that 5-HT 2C receptor agonists may dampen food reward-related responding. Furthermore, both studies report that drug effects occurred in only a subset of subjects and describe changes in fMRI BOLD signal that may enable the detection of individuals who would be most responsive to the anorectic effects of 5-HT 2C receptor agonists.…”

An attention bias test to assess anxiety states in laying hens

“…The m -CPP drug is, however, also an appetite suppressant. Humans report a reduced appetite while dosed with m -CPP (Thomas et al, 2014), but in one study it only affected consumption of a palatable snack when human subjects were already satiated (Thomas et al, 2018). Feeding behavior alone in this study is likely not sufficient to distinguish between the dosing groups, but in combination with the increased locomotion and vocalizations, the m -CPP birds could be interpreted as being more anxious following the playback of the alarm calls.…”

Multidisciplinary approaches to the study of eating disorders and obesity: Recent progress in research and development and future prospects

“…However, a recent study with another 5-HT 2C receptor agonist meta-chlorophenylpiperazine (mCPP) reported marked individual variability in both the behavioural and neural responses to mCPP in female volunteers (Thomas et al, 2017). Some participants did not reduce their intake of a palatable snack after treatment with mCPP and this lack of response was associated with enhanced ratings of snack pleasantness and enhanced baseline blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI) responses to food images in key reward and appetite circuitry (Thomas et al, 2017). Thus, further investigation of stratification of response to 5-HT 2C receptor agonists is warranted to identify individuals who are most likely to benefit from treatment with lorcaserin.…”

“…This variation in response is correlated with genetic variation in several neurotransmitter receptors, including the 5-HT 2C receptor, in addition to genes involved in obesity and metabolic disturbances. Inter-individual variation is a recurring theme in associations between 5-HT 2C receptor mechanisms (see Higgins et al, 2017; Thomas et al, 2017) and dopamine D 2 receptor mechanisms (see Evers et al, 2017) and obesity, and Reynolds and McGowan (2017) conclude that predictive genetic testing for drug-induced weight gain would be an important step forward to improve antipsychotic therapy.…”