Neural circuits of eating behaviour: Opportunities for therapeutic development.

Understanding of the neural and physiological substrates of hunger and satiety has increased rapidly over the last three decades, and pharmacological targets have already been identified for the treatment of obesity that has moved from pre-clinical screening to therapies approved by regulatory authorities. Initially, this review describes the way in which physiological signals of energy availability interact with hedonic and rewarding properties of food to modulate the neural circuitry that supports eating behaviour. This is followed by a brief account of current and promising targets for drug development and a review of the wide range of preclinical paradigms that model important influences on human eating behaviour, and can be used to guide early stages of the drug development process.

The rat's not for turning: Dissociating the psychological components of cognitive inflexibility.

Executive function is commonly assessed by assays of cognitive flexibility such as reversal learning and attentional set-shifting. Disrupted performance in these assays, apparent in many neuropsychiatric disorders, is frequently interpreted as inability to overcome prior associations with reward. However, non-rewarded or irrelevant associations may be of considerable importance in both discrimination learning and cognitive flexibility.

Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task.

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward.

Intra-accumbens baclofen, but not muscimol, increases second order instrumental responding for food reward in rats.

Stimulation of either GABA(A) or GABA(B) receptors within the nucleus accumbens shell strongly enhances food intake in rats. However the effects of subtype-selective stimulation of GABA receptors on instrumental responses for food reward are less well characterized. Here we contrast the effects of the GABA(A) receptor agonist muscimol and GABA(B) receptor agonist baclofen on instrumental responding for food using a second order reinforcement schedule.

Animal models to explore the effects of CNS drugs on food intake and energy expenditure.

Obesity has reached epidemic proportions globally with an increasing incidence not just in Western cultures but also Mexico, Brazil, China and parts of Africa. In terms of pharmacological intervention, the track record of drug treatments for obesity is poor, especially in the case of centrally acting medicines, and there remains an unmet need for the development of safer compounds delivering superior efficacy. Animal models are of importance not only in detecting changes in food intake, energy expenditure and body weight but also providing confidence that these changes are behaviourally specific and not a result of drug-induced side effects.

Hyperphagia and increased meal size are responsible for weight gain in rats treated sub-chronically with olanzapine.

Rationale: Atypical antipsychotic-induced weight gain is a significant impediment in the treatment of schizophrenia.

Objectives: In a putative model of antipsychotic drug-induced weight gain, we investigated the effects of sub-chronic olanzapine on body weight, meal patterns, the expression of genes encoding for hypothalamic feeding-related neuropeptides and the contribution of hyperphagia to olanzapine-induced weight gain in rats.

Materials And Methods: In experiment 1, female rats received either olanzapine (1 mg/kg, p.

WO03/062224 is an in vivo selective agonist at nicotinic beta4 receptors.

Pharmacological agents that increase cholinergic transmission have considerable use in cognitive disorders and evidence from both human and animal studies suggests that nicotinic acetylcholine receptors (nAChRs) represent an attractive target for treating certain neurological disorders. This investigation aimed to provide an in vivo verification of the in vitro data on WO03/062224, an agonist selective at beta4 subunit-containing nicotinic receptors. The effects of WO03/062224 were tested on wildtype and beta4 nAChR null mice on two behavioural paradigms; locomotor behaviour and instrumental responding for food on a second order schedule.

Comparative effects of olanzapine and ziprasidone on hypophagia induced by enhanced histamine neurotransmission in the rat.

Atypical antipsychotic drugs (AAPDs), such as olanzapine, are associated with weight gain and hyperphagia in both humans and rodents. This side effect, however, is absent or reduced for AAPD such as ziprasidone. The increased levels of appetite seen in rodents may be related to drug interactions with brain histamine systems involved in appetite control.

Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways.

The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT(2C)R) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT(2C)R agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass.

5-HT(2C) receptor activation inhibits appetitive and consummatory components of feeding and increases brain c-fos immunoreactivity in mice.

5-Hydroxytryptamine (5-HT)(2C) and 5-HT(1B) receptors are implicated in the inhibitory modulation of feeding behaviour. However, their respective, and possibly different, roles have not been clearly identified because of a lack of selective 5-HT(2C) receptor agonists. Here, using the putative, selective 5-HT(2C) receptor agonist VER23779, we show that its effects on feeding are fully reversed by pretreatment with a selective 5-HT(2C) receptor antagonist, but unaffected by pretreatment with either a 5-HT(1B) or a 5-HT(2A) receptor antagonist.

A comparison of the effects of the CB(1) receptor antagonist SR141716A, pre-feeding and changed palatability on the microstructure of ingestive behaviour.

Rationale: The cannabinoid CB(1) receptor inverse agonist SR141716A (rimonabant) is known to cause hypophagia and this study uses microstructural data to elucidate the relevant behavioural mechanisms.

Objectives: The aim of these studies was to determine the behavioural changes induced by SR141716A in animals consuming either a fat or carbohydrate solution. These behavioural changes were directly compared with those induced by behavioural manipulations that modify motivational state and palatability.

Serotonin reciprocally regulates melanocortin neurons to modulate food intake.

The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors.

The cannabinoid CB1 receptor inverse agonist, rimonabant, modifies body weight and adiponectin function in diet-induced obese rats as a consequence of reduced food intake.

The cannabinoid CB1 receptor inverse agonist rimonabant induces hypophagia and body weight loss. Reduced body weight may potentially be due to decreased food intake or to direct metabolic effects of drug administration on energy expenditure. This study uses a paired-feeding protocol to quantify the contributions of energy intake to rimonabant-induced body weight loss.

The anorectic effect of the selective dopamine D1-receptor agonist A-77636 determined by meal pattern analysis in free-feeding rats.

Free-feeding rats meet much of their daily energy requirements by consuming food in meals during the nocturnal phase of the night/day cycle. Meal pattern analysis methodology has been developed to record the patterns of meal taken over a 24-h period, and to provide detailed information on a number of meal-related parameters. Previous work indicates that selective dopamine D1-receptor agonists reduce food intake in short-term feeding tests under the control of homeostatic or hedonic factors.

Effects of atypical antipsychotic drugs on intralipid intake and cocaine-induced hyperactivity in rats.

Clozapine and olanzapine have been shown to acutely stimulate consumption of a fat emulsion (Intralipid) by male Lister hooded rats. We initially investigated the extent of any sex difference in Intralipid hyperphagia associated with olanzapine treatment. We then examined the degree of Intralipid hyperphagia produced by a range of atypical antipsychotic drugs having different associations with human weight gain, and also determined their effects on cocaine-stimulated locomotor activity as a measure of functional dopamine antagonism in vivo.

The cannabinoid CB1 receptor antagonist SR141716A reduces appetitive and consummatory responses for food.

Rationale: The CB1 receptor antagonist SR141716A reduces food intake in rats. This effect is likely to depend on modulation of reward related processes.

Objective: To investigate the effects of SR141716A on responding for food under a second order instrumental task in which responding and consumption of food can be separated, and on Pavlovian responding for a stimulus predictive of food reward.

Tonic regulation of satiety by 5-HT receptors in the mouse: converging evidence from behavioural and c-fos immunoreactivity studies?

Activation of 5-HT(1B) receptors is thought to play an important role in the inhibitory influence of serotonin on feeding behaviour and body weight in mammals. Earlier studies have shown that 5-HT(1B)-knockout (KO) mice eat more and are heavier than wild-type (WT) controls and that the selective 5-HT(1B) receptor agonist CP-94,253 reduces food intake in food-deprived mice. Here we characterize the behavioural effects of both CP-94,253 and the selective 5-HT(1B) receptor antagonist SB224289 on feeding and other behaviours within the behavioural satiety sequence, and also report a c-fos mapping study using CP-94,253.

Reduced hypophagic effects of d-fenfluramine and the 5-HT2C receptor agonist mCPP in 5-HT1B receptor knockout mice.

Rationale: The possible role of compensatory changes in 5-HT2C receptors in the reduced hypophagic action of d-fenfluramine in 5-HT1B knockout (KO) mice was assessed by comparing their response to d-fenfluramine and the 5-HT2C receptor agonist mCPP. In addition we measured 5-HT(2C/A) receptor binding in 5-HT1B KO and wild-type (WT) mice and examined the effects of 5-HT1B receptor antagonists on d-fenfluramine-induced hypophagia in WT mice.

Methods: Hypophagic responses to d-fenfluramine (1-30 mg/kg) and mCPP (1-5.

Serotonergic and histaminergic mechanisms involved in intralipid drinking?

Some newer antipsychotic agents are associated with weight gain in humans and a hyperphagic response to intralipid solutions in rodents. To examine the possible contribution of serotonin (5-HT) and histamine (H) receptor blockade in antipsychotic-associated hyperphagia, rats were trained to drink a palatable, high-calorie fat emulsion (10% intralipid) during 30-min sessions and were tested following pretreatment with mepyramine (H1 receptor antagonist), metergoline (5-HT(1/2) receptor antagonist), cyproheptadine (H1 and 5-HT(2A/2B/2C) and muscarinic receptor antagonist), SB 242084 (5-HT2C receptor antagonist) and an SB 242084-mepyramine combination. Total intake and ingestive behaviour microstructure were measured.

Effects of clozapine, olanzapine and haloperidol on the microstructure of ingestive behaviour in the rat.

Rationale: Antipsychotic drugs, particularly the newer atypical compounds, have been associated with rapid weight gain in a clinical setting. However, there are few reported animal models producing reliable hyperphagia correlating with the human weight gain liability of these drugs.

Objective: To compare the effects of the classic neuroleptic haloperidol with the atypical antipsychotics clozapine and olanzapine on the microstructure of ingestive behaviour in rats.

5-HT1B receptor knockout mice show a compensatory reduction in 5-HT2C receptor function.

Although null mutant ('knockout') mice have provided valuable animal models to complement traditional approaches to psychopharmacology, such animals may also show complex adaptations to the induced mutation. Here we demonstrate that serotonin1B (5-HT1B) receptor knockout (KO) mice show adaptations in serotonin2C (5-HT2C) receptor-mediated functions. They show smaller reductions in food intake and locomotor activity in response to administration of 5-HT2C receptor agonists that are not accounted for by altered drug disposition.

5-HT1B receptors modulate components of satiety in the rat: behavioural and pharmacological analyses of the selective serotonin1B agonist CP-94,253.

Rationale: 5-HT(1B) receptors are thought to be one of the receptor subtypes that mediate the inhibitory control of serotonin on food intake and satiety.

Objective: To use the selective 5-HT(1B) receptor agonist, CP-94,253 as a probe of 5-HT(1B) receptor function in feeding behaviour, and to confirm the pharmacological selectivity of CP-94,253-induced hypophagia with a range of antagonists.

Methods: Dose-response functions for CP-94,253 (0, 1.

Serotonin 2C receptor agonists and the behavioural satiety sequence in mice.

The studies reported here examined the role of the 5-hydroxytryptamine (5-HT)(2C) receptor subtype in the control of ingestive behaviour in mice. Behavioural satiety sequence (BSS) and food intake measurements were taken, comparing the selective 5-HT(2C) receptor agonist (S)-2-(6-chloro-5-fluoro-indol-l-yl)-l-methylethylamine hydrochloride (Ro 60-0175; 1.0, 3.

Meal patterns of free feeding rats treated with clozapine, olanzapine, or haloperidol.

Selective dopamine D(2) antogonists increase meal size and decrease the rate of feeding within a meal. Three experiments investigated the extent to which the atypical antipsychotics, clozapine and olanzapine, and the prototypical antipsychotic, haloperidol, affected meal size and feeding rate. Microstructural analyses of meal patterning were made over a range of drug doses administered to free feeding male Lister hooded rats.