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.
Highlights
Recent work on the neurophysiological basis of eating behaviour suggests that there are close interactions between the homeostatic networks that respond to changes in metabolic state and those involved in assigning reward value to motivational stimuli and translating motivation into action (Berthoud 2011)
These 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
We investigate for the first time the effect of the preferential 5-HT2C receptor agonist meta-chlorophenylpiperazine on hedonic eating and neural responses to food images using functional magnetic resonance imaging. mCPP is known to reduce appetite in humans (Cowen et al 1995; Walsh et al 1994; Thomas et al 2014) but to probe reward-related effects of mCPP, we examine the effect of mCPP on the consumption of a staple meal consumed in a hungry state and a palatable high-energy dense snack food eaten in the absence of hunger
Summary
Recent work on the neurophysiological basis of eating behaviour suggests that there are close interactions between the homeostatic networks that respond to changes in metabolic state and those involved in assigning reward value to motivational stimuli and translating motivation into action (Berthoud 2011). Psychopharmacology (2018) 235:257–267 value of food, which is reflected in enhanced responses to appetitive stimuli in reward-related brain areas whereas satiation decreases responses in reward-related circuitry (Goldstone et al 2009; Thomas et al 2015; see van der Laan et al 2011 for a meta-analysis) These effects are likely to be mediated by the action of metabolic signals such as leptin, insulin, peptide YY (PYY) and ghrelin on the activity of the mesocorticolimbic dopamine system (Batterham et al 2007; Guthoff et al 2010; Farooqi et al 2007; Malik et al 2008). These preclinical data suggest a specific role for 5-HT2C receptor activation in linking hypothalamic energy-sensing mechanisms to motivational aspects of eating behaviour. To date, no mechanistic studies on the effects of 5-HT2C receptor agonists on food intake in humans have been reported
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