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RATIONALE: Brain 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. OBJECTIVES: The 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. METHODS: In 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. RESULTS: mCPP 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. CONCLUSIONS: 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.

Rationale Brain 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. Objectives The 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. Methods In 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. Results mCPP 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. Conclusions 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. Electronic supplementary material The online version of this article (10.1007/s00213-017-4764-9) contains supplementary material, which is available to authorized users.

The monoamine reuptake inhibitor sibutramine reduces food intake but the receptor subtypes mediating the effects of sibutramine on feeding remain to be clearly identified.The involvement of the 5-HT(2C) receptor subtype in the satiety-enhancing effects of sibutramine was investigated by examining the effects of co-administration of sibutramine with the selective 5-HT(2C) receptor antagonist SB 242084Microstructural analyses of licking for a glucose solution by non-deprived, male rats were performed over a range of doses of sibutramine to identify a selective satiety-enhancing dose (experiment 1). Similar analyses were performed after administration of a vehicle control, two doses of SB 242084 alone or two doses of SB 242084 in combination with sibutramine (experiment 2).Sibutramine at doses of 1-3 mg/kg selectively reduced glucose consumption via a reduction in the number of bouts of licking. Non-selective effects to increase latency to lick were only observed at the higher dose of 6 mg/kg. Co-administration of sibutramine (3 mg/kg) with SB 242084 (1 or 3 mg/kg) reversed the effect of sibutramine on bout number whereas either dose of SB 242084 alone had no significant effect.We confirm behaviourally selective effects of sibutramine on feeding and provide further support for the satiety-enhancing effects of sibutramine. Our data also provide evidence for the involvement of the 5-HT(2C) receptor in the satiety-enhancing effects of sibutramine although additional targets may have an impact, and further investigation of the molecular mechanisms underlying the efficacy of sibutramine as an anorectic is warranted.

Cigarette smoking is highly prevalent in people diagnosed with depression, and depressed smokers are less likely to quit. Examining depressed smokers’ responses to smoking will help determine the role of depression in maintaining cigarette smoking. To determine the psychomotor, subjective and physiological effects of cigarette smoking in currently depressed smokers versus matched controls. Fourteen currently depressed smokers and 14 never-depressed smokers, matched in age, gender, nicotine dependence and daily cigarette consumption, smoked three cigarettes at half-hourly intervals. All smokers were non-deprived. Self-reported mood and craving for cigarettes, performance on a simple reaction time task, expired-air carbon monoxide, heart rate and blood pressure were assessed before and after smoking each cigarette. Smoking topography was also assessed. Depressives and controls did not differ in terms of dependence on cigarettes or expired-air carbon monoxide. Topographic and cardiovascular measures were similar in depressed and control participants, suggesting that they smoke cigarettes in a similar manner. However, depressives displayed enhanced reaction time performance after the first cigarette. Positively reinforced craving was reduced after smoking each cigarette but returned to baseline levels within 30 min in depressed but not in control smokers. Depressed smokers also displayed higher levels of negatively reinforced craving. Both depressives and controls reported improved positive mood after smoking. Cigarette smoking in non-deprived depressed smokers enhances psychomotor performance and the reduction of positively reinforced craving in depressed smokers after smoking is transient, suggesting that enhanced craving may play a role in the maintenance of smoking in depression.

Individual differences in responsiveness to caffeine occur even within a caffeine-consuming population, but the factors that mediate differential responsiveness remain unclear.To compare caffeine's effects on performance and mood in a group of high vs moderate consumers of caffeine and to examine the potential role of subjective awareness of the effects of caffeine in mediating any differential responsiveness.Two groups of regular caffeine consumers (200 mg/day and200 mg/day) attended two sessions at which mood and cognitive functions were measured before and 30 min after consumption of 400-mg caffeine or placebo in a capsule. Cognitive tests included visual information processing, match-to-sample visual search (MTS) and simple and choice reaction times. Post-session questionnaires asked participants to describe any perceived effect of capsule consumption.High consumers, but not moderate consumers, demonstrated significantly faster simple and choice reaction times after caffeine relative to placebo. These effects were not attributable to obvious group differences in withdrawal or tolerance because there were no group differences in baseline mood or in reports of negative affect after caffeine. Instead, the high consumers were more likely to report experiencing positive effects of caffeine, whereas the moderate consumers were more likely to report no effect.The sensitivity of caffeine consumers to the mood- and performance-enhancing effects of caffeine is related to their levels of habitual intake. High caffeine consumers are more likely than moderate consumers to perceive broadly positive effects of caffeine, and this may contribute to their levels of use.

RATIONALE: The treatment of obesity is an increasing global health priority, yet few effective drug treatments are currently available. The discovery of novel anti-obesity therapies could be assisted by the validation of experimental (translational) medicine models in healthy volunteers that assess efficacy and safety at an early stage of drug development. OBJECTIVES: The aim of this study was to examine the effects of the 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) in an experimental medicine model assessing both appetite and mood. METHODS: Using a between-subjects, double-blind, placebo-controlled design, 24 male and 24 female participants were randomly assigned to either placebo, 15- or 30-mg mCPP treatment groups. Lunch was eaten from a Universal Eating Monitor (UEM) that measured eating rate, and the participants completed the P1vital® Oxford Emotional Test Battery (ETB) and a series of appetite and mood ratings. RESULTS: mCPP reduced appetite and, in women, enhanced measures of satiation. The drug also enhanced memory for emotional material in the word recall and recognition memory tasks of the ETB. CONCLUSIONS: The results provide new insight into the effects of mCPP on appetite, satiety and memory in humans. In addition, our data provide an illustration of the value of measuring changes in appetite and mood in healthy volunteers to determine the potential efficacy and safety of novel anti-obesity drugs.

RATIONALE: The 5-HT transporter (5-HTT) is implicated in the regulation of appetite. Expression of the 5-HTT varies in the human population, and this variation may determine both individual differences in feeding and abnormal feeding behaviours such as eating disorders. OBJECTIVES: The effects of 5-HTT expression on feeding and satiety were examined in a transgenic mouse model of 5-HTT overexpression. MATERIALS AND METHODS: We measured free-feeding food intake and observed the behavioural satiety sequence (BSS) after food deprivation in mice at baseline and after administration of the anorectic drug fenfluramine. RESULTS: 5-HTT overexpressing mice were both lighter and shorter than their wildtype littermates. Despite this size difference, food intake by transgenic and wildtype mice did not differ. There was no effect of genotype on the BSS or on food intake during the test at baseline. Increasing doses of fenfluramine reduced food intake in a similar manner in both transgenic and wildtype mice. After 0.3 and 1 mg/kg fenfluramine, the temporal pattern of the BSS was the same for both groups, whereas 3 and 10 mg/kg fenfluramine disrupted the BSS. In transgenic mice, this disruption was evident at the 3 mg/kg dose, while in wildtypes, it emerged only at the 10-mg/kg dose. CONCLUSION: These data suggest that overexpression of the 5-HTT does not lead to alterations in feeding or satiety in food-deprived mice but does increase the occurrence of other non-feeding behaviours in response to the 5-HT releasing agent fenfluramine.

Rationale. Central cannabinoid systems have been implicated in appetite control through the respective hyperphagic and anorectic actions of CB1 agonists and antagonists. The motivational changes underlying these actions remain to be determined, but may involve alterations to food palatability. Objectives. The mode of action of cannabinoids on ingestion was investigated by examining the effects of exogenous and endogenous agonists, and a selective CB1 receptor antagonist, on licking microstructure in rats ingesting a palatable sucrose solution. Methods. Microstructural analyses of licking for a 10% sucrose solution was performed over a range of agonist and antagonist doses administered to non-deprived, male Lister hooded rats. Results. Δ9-tetrahydrocannabinol (0.5, 1 and 3 mg/kg) and anandamide (1 mg/kg and 3 mg/kg) significantly increased total number of licks. This was primarily due to an increase in bout duration rather than bout number. There was a non-significant increase in total licks following administration of 2-arachidonoyl glycerol (0.2, 1.0 and 2.0 mg/kg), whereas administration of the CB1 antagonist SR141716 (1 mg/kg and 3 mg/kg) significantly decreased total licks. All drugs, with the exception of anandamide, significantly decreased the intra-bout lick rate. An exponential function fitted to the cumulative lick rate curves for each drug revealed that all compounds altered the asymptote of this function without having any marked effects on the exponent. Conclusions. These data are consistent with endocannabinoid involvement in the mediation of food palatability.

The behavioural mechanisms underlying the effects of the opioid antagonist naloxone (0.3-3 mg/kg i.p.), and the opioid agonists morphine (0.3-3 mg/kg s.c.), and U-50, 488H (0.3-3 mg/kg s.c.) on ingestive behaviour were investigated using a microstructural analysis of licking patterns for sucrose solutions and Intralipid (fat emulsions) in a brief contact test. Naloxone dose-dependently decreased the total number of licks and the number of bouts for sucrose and Intralipid, but did not affect mean bout duration. Morphine dose-dependently increased the total number of licks and the number of bouts for both test fluids. For Intralipid but not for sucrose drinking, morphine actually decreased mean bout duration. U-50, 488H significantly affected total licks, although the dose-effect relationship showed an inverted U-shaped function. There was a dose-dependent increase in mean bout duration following administration of U-50, 488H and an increase in bout number, although only the lowest dose differed significantly from the control condition. The results show that microstructural analysis can distinguish between the effects of naloxone, morphine and U-50, 488H on licking behaviour and indicate that selective opioid receptor subtypes may be differentially involved in ingestive processes.

The role of endogenous opioid peptides in the effects of midazolam on ingestive behaviour was investigated using a detailed analysis of licking behaviour in the rat. Midazolam (1.8 mg/kg i.p.) was administered in combination with either flumazenil (10 and 20 mg/kg i.p.) or naloxone (0.1 and 0.3 mg/kg i.p.). The effect on licking patterns during 60-s exposures to a range of concentrations of a fat emulsion (Intralipid) was then recorded. Midazolam significantly increased the total number of licks for Intralipid by increasing the mean bout duration. This effect is consistent with the proposal that benzodiazepines enhance palatability. Flumazenil and naloxone were ineffective when administered alone, but both drugs blocked the effect of midazolam on total number of licks by selectively attenuating mean bout duration. Midazolam also produced a significant decrease in the intrabout lick rate, probably due to the muscle relaxant effects of this drug. This decrease in the intrabout lick rate was reversed by pretreatment with flumazenil but not by naloxone. The results suggest that endogenous opioids may be important for the palatability effects of midazolam, but may not be involved in the muscle relaxant effects of this drug.

Rationale Whilst the FDA-approved anorectic, lorcaserin and various 5-hydroxytryptamine (5-HT)6 receptor antagonists reduce feeding, a direct assessment of their impact upon feeding behaviour is less clear. We therefore examined the action of lorcaserin and the clinical-stage developmental candidate 5-HT6 receptor antagonist, SB-742457, upon microstructural analysis of licking behaviour. Such analysis provides a rich source of information about the mechanisms controlling food intake. Objectives The objective of the present study was to gain insight into the influence upon feeding behaviour of the 5-HT2C receptor agonist, lorcaserin and the developmental 5-HT6 receptor antagonist, SB-742457. Methods The impact of lorcaserin and SB-742457 upon licking behaviour of non-deprived rats for a glucose solution was assessed using microstructural analysis. Results Lorcaserin (0.1–3.0 mg/kg) displayed a dose-dependent ability to reduce glucose consumption via reduction in the number of bouts of licking. A similar action was evident with SB-742457, but only at the lowest dose tested (3.0 mg/kg). Conclusions The behavioural actions of both lorcaserin and SB-742457 demonstrate they directly promote satiety.