5-HT1B receptors modulate the feeding inhibitory effects of enterostatin (original) (raw)
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Behavioural Brain Research
Although serotonin (5-HT) signaling is known to regulate food intake and energy homeostasis, the roles of the 5-HT 3 receptor in feeding processes has been elusive. 5-HT 3 receptors are found throughout mesolimbic circuitry that promote feeding not only in response to hunger, but also to the palatable and rewarding properties of food. These experiments examined if stimulation or blockade of the 5-HT 3 receptor of the nucleus accumbens (NAcc) or ventral tegmentum affected food intake in the rat in response to hunger or the presence of a palatable diet. Rats (N = 6-9/ group) received bilateral injections of the 5-HT 3 agonist m-chlorophenylbiguanide hydrochloride (mCPBG; at 0.0, 10.0, or 20.0 µg/0.5µl/side) or the 5-HT 3 antagonist ondansetron hydrochloride (at 0.0, 1.0, 2.0, or 5.0 µg/0.5µl/side) into either the NAcc or the ventral tegmentum. NAcc 5-HT 3 receptor stimulation significantly increased 2-hr food intake in food-deprived animals offered rat chow and in a separate group of unrestricted rats offered a sweetened fat diet. In contrast to the feeding increase seen with NAcc treatments, stimulation of 5-HT 3 receptors of the ventral tegmentum significantly reduced food and water intake in food-restricted animals; reductions of intake in non-restricted rats offered the palatable diet did not approach significance. Blockade of the 5-HT 3 receptor had no effect on feeding in either brain region. These data support a functional role for serotonergic signaling in the mesolimbic pathway on motivated behavior, and demonstrate that 5-HT 3 receptors differentially modulate food consumption in a region-dependent manner.
Journal of Neuroscience, 2013
An essential component of the neural network regulating ingestive behavior is the brain 5-hydroxytryptamine2C receptor (5-HT 2C R), agonists of which suppress food intake and were recently approved for obesity treatment by the US Food and Drug Administration. 5-HT 2C R-regulated appetite is mediated primarily through activation of hypothalamic arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons, which are also disinhibited through a 5-HT 1B R-mediated suppression of local inhibitory inputs. Here we investigated whether 5-HT 2C R agonist anorectic potency could be significantly enhanced by coadministration of a 5-HT 1B R agonist and whether this was associated with augmented POMC neuron activation on the population and/or single-cell level. The combined administration of subanorectic concentrations of 5-HT 2C R and 5-HT 1B R agonists produced a 45% reduction in food intake and significantly greater in vivo ARC neuron activation in mice. The chemical phenotype of activated ARC neurons was assessed by monitoring agonist-induced cellular activity via calcium imaging in mouse POMC-EGFP brain slices, which revealed that combined agonists activated significantly more POMC neurons (46%) compared with either drug alone (ϳ25% each). Single-cell electrophysiological analysis demonstrated that 5-HT 2C R/5-HT 1B R agonist coadministration did not significantly potentiate the firing frequency of individual ARC POMC-EGFP cells compared with agonists alone. These data indicate a functional heterogeneity of ARC POMC neurons by revealing distinct subpopulations of POMC cells activated by 5-HT 2C Rs and disinhibited by 5-HT 1B Rs. Therefore, coadministration of a 5-HT 1B R agonist potentiates the anorectic efficacy of 5-HT 2C R compounds by increasing the number, but not the magnitude, of activated ARC POMC neurons and is of therapeutic relevance to obesity treatment.
Serotonergic control of the organization of feeding and satiety
Behavioural Brain Research, 1995
Studies in which serotonergic drugs were administered either systemically or directly into central sites have implicated 5-HT in the inhibitory control of feeding in mammals. In animal models and in humans, 5-HT agonists such as fenfluramine, fluoxetine and sertraline reduced the rate of eating and the size of meals in a manner suggesting that increasing serotonergic neurotransmission specifically enhanced satiation. In rodents, directly acting agonists at 5-HT1B, 5-HT2c or 5-HT2A receptors decreased food intake but by different behavioral mechanisms. Stimulation of the 1B and 2C subtypes may probe physiological roles in feeding and satiety. The former receptors may be involved primarily in regulating meal size and the latter more in controlling eating rate. Activation of both may be required for complete expression of behavioral satiety. By contrast, stimulating 2A sites may simply disrupt the continuity of feeding. Drugs that stimulate 5-HT1A autoreceptors increase food intake, presumably by acutely reducing the firing of serotonergic neurons in the brain. The hypothalamic paraventricular nucleus (PVN) has been proposed as an important terminal field in the forebrain that is involved in 5-HT's satiety role although recent studies implicate extra-PVN regions in this function. Peripherally administered 5-HT also decreases food intake in rats in a behaviorally specific manner. Studies with antagonists and with structural analogs of 5-HT revealed that 5-HT's peripheral satiety action involves 5-HTa-like and 5-HT2like mechanisms. Thus, within and outside the brain, multiple pharmacological and behavioral mechanisms contribute to serotonergic functions in ingestion. The rich body of data from preclinical investigation in animals provides the foundation for therapeutic development in humans.
Psychopharmacology, 2002
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, 1.25, 2.5, 5.0 mg/kg; IP) were determined in animals consuming wet mash in a 40-min test session during which time-sampled behavioural observations were collected to evaluate satiety sequences. A meal patterning study was carried out in a separate group of rats. The 5-HT 1A antagonist WAY 100,635 (0, 1.0, 3.0 mg/kg; SC), the 5-HT 1B/1D antagonist GR 127,935 (0, 3 mg/kg; IP), and the 5-HT 1B antagonist SB 224289 (0, 2.5, 5.0 mg/kg; IP) were used to confirm that 5-HT 1B receptor subtypes were responsible for the action of CP-94,253 on feeding behaviour. Results: CP-94,253 (2.5 mg/ kg) reduced food intake and preserved the satiety sequence in animals consuming a diet of mash. GR 127,935 (3.0 mg/kg) and SB 224289 (2.5 mg/kg), but not WAY 100,635, attenuated the hypophagic effect of the 5-HT 1B agonist, and returned the changes in satiety sequence to control patterns. Meal patterning analyses indicated that CP-94,253 (2.5 mg/kg) reduced food intake through a decrease in meal size and duration in the absence of any alteration in the rate of eating. A hypodipsic action of CP-94,253 was also observed (2.5 and 5.0 mg/kg). Conclusion: These findings imply that 5-HT 1B receptors regulate discrete elements of satiety. We discuss the potential role of 5-HT 1B agonists for the treatment of obesity.
Gastrointestinal hormones regulating appetite
Philosophical Transactions of the Royal Society B: Biological Sciences, 2006
The role of gastrointestinal hormones in the regulation of appetite is reviewed. The gastrointestinal tract is the largest endocrine organ in the body. Gut hormones function to optimize the process of digestion and absorption of nutrients by the gut. In this capacity, their local effects on gastrointestinal motility and secretion have been well characterized. By altering the rate at which nutrients are delivered to compartments of the alimentary canal, the control of food intake arguably constitutes another point at which intervention may promote efficient digestion and nutrient uptake. In recent decades, gut hormones have come to occupy a central place in the complex neuroendocrine interactions that underlie the regulation of energy balance.
Brain Research, 1992
A variety of evidence has led to suggestions that brain serotonin (5-HT) and norepinephrine (NE) interact within the medial hypothalamus to control food intake. To test the possibility that chronic decrements in 5-HT might enhance NE-induced feeding, adult male rats were prepared with permanently indwelling cannulae aimed at the paraventricular nucleus (PVN), then received either intracisternal (IC) or PVN injections of the 5-HT neurotoxin, 5,7-dihydro~tryptamine (5,7-DHT) vs. its vehicle, !% ascorbic acid. Over a 4-week period, IC-5,7-DHT rats showed no signs of enhanced daily feeding or drinking. However, in 40-min intake tests, feeding but not drinking was enhanced by injecting 20 nmol NE into the PVN commencing 2 weeks after neurotoxin treatment. Terminal monoamine assays confirmed that IC-50-DHT produced large (80-90%) depletions of brain regional 5-HT. A functional index of 5-HT terminal damage was also implied by the impaired short-term feeding responses IC-5,7-DHT rats showed to the systemic administration of the 5-HTIA agonist, 8-hydroxy-2.(di.n.propylamino) tetralin (8-OH-DPAT) when tested between 3 and 4 weeks after IC treatment. Over a comparable 4-week period, PVN-5,7-DHT rats also showed no tendencies to overeat or overdrink on a daily basis. However, in contrast to IC-5,7-DHT rats, they also showed no differences in their feeding or drinking responses to NE injections into the PVN. This was so despite reliable depletions of 5-HT in the hypothalamus (-28%) and hippocampus (-71%). These results support earlier work showing that neither widespread nor localized hypothalamic damage to brain 5-HT neurons produce chronic overeating. However, the data suggest that phasic enhancements of PVN NE activity may trigger enhanced feeding when there is widespread damage to brain 5-HT neurons, although the PVN does not appear to be the brain site mediating this effect.
Serotonin3 receptors in gastric mechanisms of cholecystokinin-induced satiety
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2006
OUR UNDERSTANDING OF THE CONTROLS of food intake has increased substantially during the last 30 years. Important in this has been the recognition of the meal as a controlled, physiologically relevant unit of energy intake. During a meal, ingested nutrients accumulate in the stomach and gradually pass to the small intestine. The gastrointestinal presence of nutrients stimulates the release of peptides and neurotransmitters that coordinate gastrointestinal secretion and motility to facilitate digestion. These events can individually, and in concert, produce signals to the brain that lead to meal termination or satiety (28) and thus determine individual meal size. The gut-brain peptide cholecystokinin (CCK) and the monoamine serotonin (5-HT) are two long-recognized agents of satiation. In this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Hayes et al. (16) present important new information about how CCK and 5-HT systems interact to promote peripheral mechanisms of satiety.
5-HT 1A receptor activation is necessary for 5-MeODMT-dependent potentiation of feeding inhibition
We propose a translational approach to the study of anorexia nervosa (AN) based on our human subject studies where there are characteristic elevations in 5-HT 1A receptor binding, associated harm avoidance behaviors, reduced impulsivity, and comorbid anxiety disorders. Towards this goal, the hyponeophagia assay was implemented whereby food-deprived mice show increased latency to begin feeding in a novel, anxiogenic environment. The non-selective serotonin agonist, 5-MeODMT, potentiates feeding inhibition compared to the inhibition generated by the anxiogenic environment in a drug-by-environment interaction. Thus, using hyponeophagia in mice, it was possible to study the following key components of AN: anxiety; feeding inhibition; and a modulatory role of the serotonergic system. A major prediction of the proposed AN model is that 5-HT 1A receptor activation is necessary for feeding inhibition. In support of this model, the 5-HT 1A receptor antagonist, WAY100635, reverses the 5-MeODMT-dependent potentiation of feeding inhibition. Our findings hint at a mechanistic role for increased 5-HT 1A receptor activation in restricting-type AN. Further implications for the interplay between anxiety and feeding inhibition in AN are discussed.