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The atypical antipsychotic drug clozapine has multiple pharmacological actions, some of which, including 5-hydroxytryptamine (5-HT2) and histamine (H1) receptor antagonist effects, are shared by the non-selective 5-HT receptor antagonist cyproheptadine. Atypical antipsychotics have a characteristic profile of action on operant behaviour maintained by progressive ratio schedules, as revealed by Killeen’s (1994) mathematical model of schedule controlled behaviour. These drugs increase the values of a parameter that expresses the ‘incentive value’ of the reinforcer (a) and a parameter that is inversely related to the ‘motor capacity’ of the organism (δ). This experiment examined the effects of acute treatment with cyproheptadine and clozapine on performance on a progressive ratio schedule of food reinforcement in rats; the effects of a conventional antipsychotic, haloperidol, and two drugs with food intake-enhancing effects, chlordiazepoxide and Δ9-tetrahydrocannabinol (THC), were also examined. Cyproheptadine (1, 5 mg kg−1) and clozapine (3.75, 7.5 mg kg−1) increased a and δ. Haloperidol (0.05, 0.1 mg kg−1) reduced a and increased δ. Chlordiazepoxide (3, 10 mg kg−1) increased a but reduced δ. THC (1, 3 mg kg−1) had no effect. Interpretation based on Killeen’s (1994) model suggests that cyproheptadine and clozapine enhanced the incentive value of the reinforcer and impaired motor performance. Motor impairment may be due to sedation (possibly reflecting H1 receptor blockade). Enhancement of incentive value may reflect simultaneous blockade of H1 and 5-HT2 receptors, which has been proposed as the mechanism underlying the food intake-enhancing effect of cyproheptadine. In agreement with previous findings, haloperidol impaired motor performance and reduced the incentive value of the reinforcer. Chlordiazepoxide’s effect on a is consistent with its food intake-enhancing effect. [ABSTRACT FROM PUBLISHER]

It has been suggested that a sub-population of orexinergic neurones whose somata lie in the lateral hypothalamic area (LHA) play an important role in regulating the reinforcing value of both food and drugs. This experiment examined the effect of disruption of orexinergic mechanisms in the LHA on performance on the progressive ratio schedule of reinforcement, in which the response requirement increases progressively for successive reinforcers. The data were analysed using a mathematical model which yields a quantitative index of reinforcer value and dissociates effects of interventions on motor and motivational processes. Rats were trained under a progressive ratio schedule using food-pellet reinforcement. They received bilateral injections of conjugated orexin-B-saporin (OxSap) into the LHA or sham lesions. Training continued for a further 40 sessions after surgery. Equations were fitted to the response rate data from each rat, and the parameters of the model were derived for successive blocks of 10 sessions. The OxSap lesion reduced the number of orexin-containing neurones in the LHA by approximately 50% compared with the sham-lesioned group. The parameter expressing the incentive value of the reinforcer was not significantly altered by the lesion. However, the parameter related to the maximum response rate was significantly affected, suggesting that motor capacity was diminished in the OxSap-lesioned group. The results indicate that OxSap lesions of the LHA disrupted food-reinforced responding on the progressive ratio schedule. It is suggested that this disruption was brought about by a change in non-motivational (motor) processes. [ABSTRACT FROM PUBLISHER]

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated; however, the neuronal substrates involved are poorly understood., Methods: We employed a combination of neuroanatomical, genetic, and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain., Results: We found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs and for the induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance., Conclusions: In addition to disclosing a neuronal population required for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea - a major factor for withdrawal from treatment., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT 2C R) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved., Methods: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control., Results: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4R ChAT ) to exert its effects on glucose homeostasis. In contrast, MC4R ChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity., Conclusions: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease., (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.)

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-HT 2C R) is a target for the treatment of human obesity. Mechanistically, 5-HT 2C Rs 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-HT 2C Rs in incentive motivation using a mathematical model of progressive ratio (PR) responding in mice. We found that the 5-HT 2C R agonist lorcaserin significantly reduced both ad libitum chow intake and PR responding for chocolate pellets and increased c-fos expression in VTA 5-HT 2C R expressing γ-aminobutyric acid (GABA) neurons, but not 5-HT 2C R expressing dopamine (DA) neurons. We next adopted a chemogenetic approach using a 5-HT 2C R CRE line to clarify the function of subset of 5-HT 2C receptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT 2C 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-HT 2C receptor expressing neurons had no effect on the feeding behavior. These results indicate that activation of the subpopulation of 5-HT 2C R neurons within the VTA is sufficient to significantly reduce homeostatic feeding and effort-based intake of palatable food, and that this subset has an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity.

Background: Neural networks that regulate binge eating remain to be identified, and effective treatments for binge eating are limited., Methods: We combined neuroanatomic, pharmacologic, electrophysiological, Cre-lox, and chemogenetic approaches to investigate the functions of 5-hydroxytryptamine (5-HT) 2C receptor (5-HT 2C R) expressed by dopamine (DA) neurons in the regulation of binge-like eating behavior in mice., Results: We showed that 5-HT stimulates DA neural activity through a 5-HT 2C R-mediated mechanism, and activation of this midbrain 5-HT→DA neural circuit effectively inhibits binge-like eating behavior in mice. Notably, 5-HT medications, including fluoxetine, d-fenfluramine, and lorcaserin (a selective 5-HT 2C R agonist), act on 5-HT 2C Rs expressed by DA neurons to inhibit binge-like eating in mice., Conclusions: We identified the 5-HT 2C R population in DA neurons as one potential target for antibinge therapies, and provided preclinical evidence that 5-HT 2C R agonists could be used to treat binge eating., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Obesity is one of the primary healthcare challenges of the 21st century. Signals relaying information regarding energy needs are integrated within the brain to influence body weight. Central among these integration nodes are the brain pro-opiomelanocortin (POMC) peptides, perturbations of which disrupt energy balance and promote severe obesity. However, POMC neurons are neurochemically diverse and the crucial source of POMC peptides that regulate energy homeostasis and body weight remains to be fully clarified., Methods: Given that a 5-hydroxytryptamine 2c receptor (5-HT2CR) agonist is a current obesity medication and 5-HT2CR agonist's effects on appetite are primarily mediated via POMC neurons, we hypothesized that a critical source of POMC regulating food intake and body weight is specifically synthesized in cells containing 5-HT2CRs. To exclusively manipulate Pomc synthesis only within 5-HT2CR containing cells, we generated a novel 5-HT 2C R (CRE) mouse line and intercrossed it with Cre recombinase-dependent and hypothalamic specific reactivatable Pomc (NEO) mice to restrict Pomc synthesis to the subset of hypothalamic cells containing 5-HT2CRs. This provided a means to clarify the specific contribution of a defined subgroup of POMC peptides in energy balance and body weight., Results: Here we transform genetically programed obese and hyperinsulinemic male mice lacking hypothalamic Pomc with increased appetite, reduced physical activity and compromised brown adipose tissue (BAT) into lean, healthy mice via targeted restoration of Pomc function only within 5-HT2CR expressing cells. Remarkably, the same metabolic transformation does not occur in females, who despite corrected feeding behavior and normalized insulin levels remain physically inactive, have lower energy expenditure, compromised BAT and develop obesity., Conclusions: These data provide support for the functional heterogeneity of hypothalamic POMC neurons, revealing that Pomc expression within 5-HT2CR expressing neurons is sufficient to regulate energy intake and insulin sensitivity in male and female mice. However, an unexpected sex difference in the function of this subset of POMC neurons was identified with regard to energy expenditure. We reveal that a large sex difference in physical activity, energy expenditure and the development of obesity is driven by this subpopulation, which constitutes approximately 40% of all POMC neurons in the hypothalamic arcuate nucleus. This may have broad implications for strategies utilized to combat obesity, which at present largely ignore the sex of the obese individual.

Rationale: It has been suggested that streptozotocin (STZ)-induced diabetes causes a motivational deficit in rodents. However, some of the evidence adduced in support of this suggestion may be interpreted in terms of a motor impairment rather than a motivational deficit., Objective: This experiment examined the effect of STZ-induced diabetes on performance on a progressive ratio schedule. The data were analysed using a new model derived from Killeen's (Behav Brain Sci 17:105-172, 1994) Mathematical Principles of Reinforcement model which enables the effects of interventions on motivation or incentive value to be separated from effects on motor function., Method: Animals were trained under a progressive ratio schedule using food-pellet reinforcement. Then they received a single intraperitoneal injection of 50 mg/kg of STZ or the vehicle. Training continued for 30 sessions after treatment. Running and overall response rates in successive ratios were analysed using the new model, and estimates of the model's parameters were compared between groups., Results: The parameter expressing incentive value was reduced in the group treated with STZ, whereas the parameters expressing motor capacity and post-reinforcement pausing were not affected by the treatment. Blood glucose concentration was significantly elevated in the STZ-treated group compared to the vehicle-treated group., Conclusions: The results are consistent with the suggestion that STZ-induced diabetes is associated with a reduction of the incentive value of food.

Previous research has provided discrepant results about how reinforcement delay and magnitude are combined to determine the value of the alternatives in concurrent-chains schedules. In the present experiment, we analyzed a possible interaction between these characteristics of reinforcement, employing a two component concurrent-chains schedule, with rats as experimental subjects. Non-independent VI schedules were presented in the initial links of each component. In the terminal links, the following pairs of delays to reinforcement were presented in 4 conditions: 2-28, 6-24, 24-6, 28-2s (fixed time schedules for a group, fixed interval schedules for the other). Magnitude of reinforcement was maintained constant within components: one pellet for one component, and four pellets for the other. The results indicated that in both groups, the sensitivity to delay - calculated according to the generalized matching law - was higher in the component with the larger reinforcer. This result is in contrast with those reported in the literature of temporal discounting with human participants., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Lesions of the orbital prefrontal cortex (OPFC) and the nucleus accumbens core (AcbC) can disrupt performance in inter-temporal choice tasks, possibly by increasing the organism's sensitivity to delay and/or magnitude of reinforcement. This experiment examined whether exposure to an inter-temporal choice would induce neuronal activation in these areas, as indicated by enhanced expression of the Fos protein. Twelve rats were trained to press levers A and B under an adjusting-delay schedule in which a response on A delivered 50 microl of a sucrose reinforcer after 2 or 18s, whereas a response on B delivered the same reinforcer after a delay that was adjusted in accordance with the rat's choices. Another 12 rats were trained under a similar schedule in which a response on A delivered an immediate reinforcer of size 20 or 180 microl, whereas a response on B delivered an immediate reinforcer whose size was adjusted in accordance with the rat's choices. A third group received training under a schedule that did not entail variation of reinforcer size or delay, or choice between reinforcers, and a control group underwent food restriction without behavioural training. Exposure to the adjusting-delay schedule was associated with enhanced Fos expression in both the OPFC and AcbC, whereas exposure to the adjusting-magnitude schedule was associated with enhanced Fos expression in the OPFC but not the AcbC, compared to the control group. The results are consistent with previous findings that implicated the AcbC and OPFC in delay discounting, and the OPFC in sensitivity to reinforcer size., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

In this experiment, we used a differential reinforcement of low rates (DRL) schedule to evaluate the performance of spontaneously hypertensive rats (SHR), Wistar Kyoto (WKY) and Wistar (WIS) rats, with the goal of dissociating the processes of timing and inhibition of responses through the use of two quantitative models: the peak deviation analysis and the temporal regulation model. The subjects were divided in two groups; the first group was exposed to 70 sessions under a DRL 10s schedule. SHR rats showed an apparent temporary deficit in the inhibition of responses process; however, no differences among strains were observed in terms of the timing process. The second group of rats was exposed to 30 sessions in DRL 10s schedule, before receiving three doses (2 mg/kg, 4 mg/kg and 8 mg/kg) of methylphenidate. The results obtained through both models were consistent and indicated that at higher drug doses, the performance of all three strains of rats deteriorated. The impulsivity exhibited by SHR during acquisition supports the idea of these rats as an adequate animal model of ADHD. In contrast, evidence against this relies on the normal temporal processing found and in the worsening effect that methylphenidate produced in the process of inhibition of responses. These mixed results suggest the necessity of exploring timing behavior of other animal models in order to find a reliable animal model of ADHD.