Control Of Ingestive Behavior Research Articles

Lingual Taste Nerve Transection Alters Food Selection, Relative Macronutrient Intake, and Meal Patterns in Rats Consuming a Cafeteria Diet without Changing Total Energy Intake.

The control of ingestive behavior is complex and involves input from many different sources, including the gustatory system. Signals transmitted via the taste nerves trigger responses that promote or discourage ingestion. The lingual taste nerves innervate 70% of taste buds, yet their role in the control of food selection and intake remarkably remains relatively underinvestigated. Here we used our custom five-item Food Choice Monitor to compare postsurgical behavioral responses to chow and a five-choice cafeteria diet (CAF) between male rats that had sham surgery (SHAM) or histologically verified transection of the chorda tympani and glossopharyngeal nerves (2NX). Compared with SHAM rats, 2NX rats ate significantly more of the high-fat CAF foods. The altered food choices led to dramatically increased fat intake and substantially reduced carbohydrate intake by 2NX vs SHAM rats. Furthermore, whether offered chow or CAF, 2NX rats ate fewer, larger meals each day. Eating rates implied that, compared with SHAM, 2NX rats were equally motivated to consume CAF but less motivated to eat chow. Even with these differences, energy intake and weight gain trajectories remained similar between SHAM and 2NX rats. Although some rats experienced CAF before surgery, contrary to our expectations, the effects of prior CAF experience on postsurgical eating were minimal. In conclusion, although total energy intake was unaffected, our results clearly indicate that information from one or both lingual taste nerves has a critical role in food selection, regulation of macronutrient intake, and meal termination but not long-term energy balance.

Impaired trigeminal control of ingestive behavior in the Prrxl1-/- mouse is associated with a lemniscal-biased orosensory deafferentation.

Although peripheral deafferentation studies have demonstrated a critical role for trigeminal afference in modulating the orosensorimotor control of eating and drinking, the central trigeminal pathways mediating that control, as well as the timescale of control, remain to be elucidated. In rodents, three ascending somatosensory pathways process and relay orofacial mechanosensory input: the lemniscal, paralemniscal, and extralemniscal. Two of these pathways (the lemniscal and extralemniscal) exhibit highly structured topographic representations of the orofacial sensory surface, as exemplified by the one-to-one somatotopic mapping between vibrissae on the animals’ face and barrelettes in brainstem, barreloids in thalamus, and barrels in cortex. Here we use the Prrxl1 knockout mouse model (also known as the DRG11 knockout) to investigate ingestive behavior deficits that may be associated with disruption of the lemniscal pathway. The Prrxl1 deletion disrupts somatotopic patterning and axonal projections throughout the lemniscal pathway but spares patterning in the extralemniscal nucleus. Our data reveal an imprecise and inefficient ingestive phenotype. Drinking behavior exhibits deficits on the timescales of milliseconds to seconds. Eating behavior shows deficits over an even broader range of timescales. An analysis of food acquisition and consummatory rate showed deficits on the timescale of seconds, and analysis of body weight suggested deficits on the scale of long term appetitive control. We suggest that ordered assembly of trigeminal sensory information along the lemniscal pathway is critical for the rapid and precise modulation of motor circuits driving eating and drinking action sequences.

Signaling in rat brainstem via Gpr160 is required for the anorexigenic and antidipsogenic actions of cocaine- and amphetamine-regulated transcript peptide.

Recent work identified Gpr160 as a candidate receptor for cocaine- and amphetamine-regulated transcript peptide (CARTp) and described its role in pain modulation. The aims of the present study were to determine if Gpr160 is required for the CARTp's ability to reduce food intake and water intake and to initially identify the distribution of Gpr160-like immunoreactivity (Gpr160ir) in the rat brain. A passive immunoneutralization approach targeting Gpr160 was used to block the behavioral effects of a pharmacological dose of CARTp in the fourth cerebroventricle (4V) of rats and to determine the importance of endogenously produced CARTp in the control of ingestive behaviors. Passive immunoneutralization of Gpr160 in the 4V blocked the actions of CARTp to inhibit food intake and water intake. Blockade of Gpr160 in the 4V, independent of pharmacological CART treatment, caused an increase in both overnight food intake and water intake. The decrease in food intake, but not water intake, caused by central injection of CARTp was demonstrated to be interrupted by prior administration of a glucagon-like peptide 1 (GLP-1) receptor antagonist. Gpr160ir was observed in several, distinct sites throughout the rat brain, where CARTp staining has been described. Importantly, Gpr160ir was observed to be present in both neuronal and nonneuronal cell types. These data support the hypothesis that Gpr160 is required for the anorexigenic actions of central CARTp injection and extend these findings to water drinking. Gpr160ir was observed in both neuronal and nonneuronal cell types in regions known to be important in the multiple pharmacological effects of CARTp, identifying those areas as targets for future compromise of function studies.

PB 19 Taste-related responses from the human nucleus accumbens and the hypothalamus obtained by invasive electrophysiology

The taste is a fundamental property of food-stuff indicating palatability and safety as well as hedonic value of a food. Animal research as well as human neuroimaging work has suggested multiple brain areas involved in the processing of taste. Here, we take advantage of the fact that deep brain stimulation in neuropsychiatric diseases has targeted brain areas that have been implicated in homeostatic (hypothalamus) and hedonic (Nucleus accumbens) control of ingestive behavior. We recorded local field potentials in patients receiving DBS of the hypothalamus (patient 1: Cluster headache, patient 2: pain) or the Nucleus accumbens (patient 3: anorexia, patient 4: obsessive compulsive disease, patient 5: depression) while the electrodes were externalized for initial testing of the stimulation parameters. Patients first indicated favorite and disliked foods. These foods were applied in the following way. The patient was asked to put the food in his/her mouth, to keep it in the mouth to taste it (during this phase LFPs were obtained), to spit it out and to rinse the mouth with water. Subsequently, the next trial was applied. LFPs were obtained in a bipolar fashion and subjected to Fast Fourier Transform (FFT).Distinct peaks in the spectrum were obtained that differentiated liked and disliked food in the hypothalamus and Ncl. accumbens, indicating that both brain structures are sensitive to the hedonic quality of the food. Further studies are needed to investigate the state (hungry, satiated) and trait (high vs. low external drive for eating) dependency of these taste-related responses.

Using Animal Models to Determine the Role of Gustatory Neural Input in the Control of Ingestive Behavior and the Maintenance of Body Weight.

Decades of research have suggested that nutritional intake contributes to the development of human disease, mainly by influencing the development of obesity and obesity-related conditions. A relatively large body of research indicates that functional variation in human taste perception can influence nutritional intake as well as body mass accumulation. However, there are a considerable number of studies that suggest that no link between these variables actually exists. These discrepancies in the literature likely result from the confounding influence of a variety of other, uncontrolled, factors that can influence ingestive behavior. In this review, the use of controlled animal experimentation to alleviate at least some of these issues related to the lack of control of experimental variables is discussed. Specific examples of the use of some of these techniques are examined. The review will close with some specific suggestions aimed at strengthening the link between gustatory neural input and its putative influence on ingestive behaviors and the maintenance of body weight.

Nesfatin‐1 influences the excitability of subfornical organ neurons through actions on the Ik conductance (1129.2)

Nesfatin‐1 is produced in several brain areas involved in metabolic processes and has been implicated in the control of ingestive behaviors and cardiovascular function. In this study, we confirm the presence of mRNA for the nucleobindin‐2 gene in the subfornical organ (SFO). We used whole‐cell patch clamp recordings in current clamp configuration to investigate the influence of nesfatin‐1 on the membrane potential of dissociated SFO neurons. We found that 80.3% (49 of 61) of neurons tested showed a response to nesfatin‐1 (100 nM, 10 nM and 1 nM) with 47.5% depolarising and 32.8% hyperpolarising. We then used voltage clamp configuration to investigate the conductances through which nesfatin‐1 may act to change the membrane potential of SFO neurons. Voltage clamp ramp and step protocols revealed a nesfatin‐1 induced enhancement of the delayed rectifier potassium conductance, IK. Pharmacological blockade of this conductance using tetraethyl ammonium chloride (TEA) greatly reduced the magnitude and occurrence of the observed hyperpolarisations, which implies that nesfatin‐1 induced hyperpolarisations are mediated through IK. This study has demonstrated that nesfatin‐1 has the ability to influence the membrane potential of SFO neurons by enhancing the IK conductance, and thus has identified the SFO as a potential site at which nesfatin‐1 may act to regulate ingestive behaviour and cardiovascular control.Grant Funding Source: Canadian Institutes for Health Research

Neuropeptide Y-induced feeding is dependent on GABAA receptors in neonatal chicks

In mammals and birds, neuropeptide Y (NPY) and gamma-aminobutyric acid (GABA) are found in brain areas known to be involved in the control of ingestive behavior and act to increase voluntary food intake. In rats, significant evidence suggest a functional and behavioral interaction between NPY and GABA mediated transmission in various brain regions, including the arcuate and paraventricular nuclei of the hypothalamus which can be important in the regulation of feeding behavior. In the present study, the effect of intracerebroventricular (ICV) administration of NPY and GABA receptor antagonists on food intake was examined in neonatal chicks. The ICV injection of NPY strongly stimulated food intake while co-administration of NPY and picrotoxin, a GABA(A) antagonist, (but not CGP54626, a GABA(B) antagonist) weakened food intake induced by NPY. These results suggest that central NPY stimulates food intake in neonatal chicks by interaction with the GABAergic system via GABA(A) receptors.

The lateral hypothalamus as integrator of metabolic and environmental needs: From electrical self-stimulation to opto-genetics

As one of the evolutionary oldest parts of the brain, the diencephalon evolved to harmonize changing environmental conditions with the internal state for survival of the individual and the species. The pioneering work of physiologists and psychologists around the middle of the last century clearly demonstrated that the hypothalamus is crucial for the display of motivated behaviors, culminating in the discovery of electrical self-stimulation behavior and providing the first neurological hint accounting for the concepts of reinforcement and reward. Here we review recent progress in understanding the role of the lateral hypothalamic area in the control of ingestive behavior and the regulation of energy balance. With its vast array of interoceptive and exteroceptive afferent inputs and its equally rich efferent connectivity, the lateral hypothalamic area is in an ideal position to integrate large amounts of information and orchestrate adaptive responses. Most important for energy homeostasis, it receives metabolic state information through both neural and humoral routes and can affect energy assimilation and energy expenditure through direct access to behavioral, autonomic, and endocrine effector pathways. The complex interplays of classical and peptide neurotransmitters such as orexin carrying out these integrative functions are just beginning to be understood. Exciting new techniques allowing selective stimulation or inhibition of specific neuronal phenotypes will greatly facilitate the functional mapping of both input and output pathways.

P.1.012 Changes in hippocampal plasticity during pregnancy and post partum are reversed by offspring separation

During the last two decades attention has been focussed on the role of different neuropeptides in hypothalamic control of feeding behavior. Several hypothalamic peptides that participate in the control of ingestive behavior are produced in neuronal cell bodies of the arcuate nucleus and/or the lateral hypothalamic area. Apart from producing orexigenic or anorexigenic compounds of peptidergic nature, these neurons also produce excitatory and inhibitory amino acid neurotransmitters. The role of GABA and glutamate in regulating energy balance has received less attention in comparison to neuropeptides. The arcuate nucleus–median eminence area, a region with a weak blood–brain barrier, contains at least two neuronal cell populations that exert opposing actions on energy balance. The majority of the neurons located in the ventromedial aspect of the arcuate nucleus, which produce the orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AGRP), contain in addition the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) and the vesicular GABA transporter (VGAT), thereby supporting their GABAergic nature. Some neurons producing pro-opiomelanocortin (POMC)- and cocaine- and amphetamine-regulated transcript (CART), located in the ventrolateral division of the arcuate nucleus have recently been reported to contain the vesicular glutamate transporter 2 (VGLUT2), a marker for glutamatergic neurons, and the acetylcholine (ACh) synthesizing enzyme choline acetyltransferase (ChAT) as well as the vesicular ACh transporter (VAChT), supporting also a cholinergic phenotype. In the lateral hypothalamic area, hypocretin/orexin neurons express VGLUT1 or VGLUT2, but not GAD, whereas some melanin-concentrating hormone (MCH) cells contain GAD. These observations support the view that several classical transmitters, relatively neglected feeding transmitters candidates, are present in key neurons that regulate body weight and consequently may represent important orexigenic/anorexigenic mediators that convey information to other neurons within the hypothalamus as well as from the hypothalamus to other brain regions that participate in regulation of energy balance.

Terminal field specificity of forebrain efferent axons to the pontine parabrachial nucleus and medullary reticular formation

The pontine parabrachial nucleus (PBN) and medullary reticular formation (RF) are hindbrain regions that, respectively, process sensory input and coordinate motor output related to ingestive behavior. Neural processing in each hindbrain site is subject to modulation originating from several forebrain structures including the insular gustatory cortex (IC), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CeA), and lateral hypothalamus (LH). The present study combined electrophysiology and retrograde tracing techniques to determine the extent of overlap between neurons within the IC, BNST, CeA and LH that target both the PBN and RF. One fluorescent retrograde tracer, red (RFB) or green (GFB) latex microbeads, was injected into the gustatory PBN under electrophysiological guidance and a different retrograde tracer, GFB or fluorogold (FG), into the ipsilateral RF using the location of gustatory NST as a point of reference. Brain tissue containing each forebrain region was sectioned, scanned using a confocal microscope, and scored for the number of single and double labeled neurons. Neurons innervating the RF only, the PBN only, or both the medullary RF and PBN were observed, largely intermingled, in each forebrain region. The CeA contained the largest number of cells retrogradely labeled after tracer injection into either hindbrain region. For each forebrain area except the IC, the origin of descending input to the RF and PBN was almost entirely ipsilateral. Axons from a small percentage of hindbrain projecting forebrain neurons targeted both the PBN and RF. Target specific and non-specific inputs from a variety of forebrain nuclei to the hindbrain likely reflect functional specialization in the control of ingestive behaviors.

Evidence from knockout mice for distinct implications of neuropeptide-Y Y2 and Y4 receptors in the circadian control of locomotion, exploration, water and food intake

Members of the neuropeptide-Y (NPY) family acting via Y2 and/or Y4 receptors have been proposed to participate in the control of ingestive behaviour and energy homeostasis. Since these processes vary between day and night, we explored the circadian patterns of locomotor, exploratory and ingestive behaviour in mice with disrupted genes for Y2 (Y2-/-) or Y4 (Y4-/-) receptors. To this end, the LabMaster system was used and its utility for the analysis of changes in circadian activity and ingestion caused by gene knockout evaluated. Female animals, aged 27weeks on average, were housed singly in cages fitted with sensors for water and food intake and two infrared frames for recording ambulation and rearing under a 12h light/dark cycle for 4days. Relative to WT animals, diurnal locomotion, exploration, drinking and feeding were reduced, whereas nocturnal locomotion was enhanced in Y2-/- mice. In contrast, Y4-/- mice moved more but ate and drank less during the photophase, while they ate more and explored less during the scotophase. Both Y2-/- and Y4-/- mice weighed more than WT mice. These findings attest to a differential role of Y2 and Y4 receptor signalling in the circadian control of behaviours that balance energy intake and energy expenditure. These phenotypic traits can be sensitively and continuously recorded by the LabMaster system.

Feeding specific glutamate surge in the rat lateral hypothalamus revealed by low-flow push–pull perfusion

Substantial evidence implicates the lateral hypothalamus (LH) in the control of ingestive behavior and previous studies have found that glutamate release within the LH increases during meals. It is not known, however, whether this effect is selective for feeding, or whether similar changes are also seen during drinking. In this work, we examined this question using low-flow push–pull perfusion which allows sampling from small tissue volumes. Presentation of highly palatable solid or liquid foods to food-deprived rats resulted in an immediate increase in glutamate output of more than 200% over baseline. The response was maximal immediately after food presentation. In contrast, significant changes in glutamate output were not seen when water was presented to water-deprived animals, despite the occurrence of vigorous drinking. These findings confirm reports of feeding related glutamate release in the LH and demonstrate that this effect is specific to feeding, rather than being a general concomitant of all ingestive behaviors. The push–pull technique described here may allow the relevant region of the LH to be identified with greater precision than other methods.

Conserved neurochemical pathways involved in hypothalamic control of energy homeostasis

The melanocortin system, which includes alpha-melanocyte-stimulating hormone (alpha-MSH) and its endogenous antagonist, agouti-related protein (AgRP), is fundamental for the central control of energy homeostasis in mammals. Recent studies have demonstrated that many neuropeptides involved in the control of ingestive behavior and energy expenditure, including melanocortins, are also expressed and functional in teleost fishes. To test the hypothesis that the underlying neural pathways involved in energy homeostasis are conserved throughout vertebrate evolution, the neuroanatomical distribution of alpha-MSH in relation to AgRP was mapped in a teleost (zebrafish, Danio rerio) by double-label immunocytochemistry. Zebrafish alpha-MSH- and AgRP-immunoreactive (ir) cells are found in discrete populations in the ventral periventricular hypothalamus, the proposed arcuate homologue in teleosts. Major ascending projections are similar for both peptides, and dense ir-fibers innervate preoptic and ventral telencephalic nuclei homologous to paraventricular, lateral septal, and amygdala nuclei in mammals. Furthermore, alpha-MSH and AgRP-ir somata and fibers are pronounced at 5 days post fertilization when yolk reserves are depleted and larvae begin to feed actively, which supports the functional significance of these peptides for feeding behavior. The conservation of melanocortin peptide function and projection pathways further support zebrafish as an excellent genetic model system to investigate basic mechanisms involved in the central regulation of energy homeostasis.

Neurotransmitters in key neurons of the hypothalamus that regulate feeding behavior and body weight

During the last two decades attention has been focussed on the role of different neuropeptides in hypothalamic control of feeding behavior. Several hypothalamic peptides that participate in the control of ingestive behavior are produced in neuronal cell bodies of the arcuate nucleus and/or the lateral hypothalamic area. Apart from producing orexigenic or anorexigenic compounds of peptidergic nature, these neurons also produce excitatory and inhibitory amino acid neurotransmitters. The role of GABA and glutamate in regulating energy balance has received less attention in comparison to neuropeptides. The arcuate nucleus–median eminence area, a region with a weak blood–brain barrier, contains at least two neuronal cell populations that exert opposing actions on energy balance. The majority of the neurons located in the ventromedial aspect of the arcuate nucleus, which produce the orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AGRP), contain in addition the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) and the vesicular GABA transporter (VGAT), thereby supporting their GABAergic nature. Some neurons producing pro-opiomelanocortin (POMC)- and cocaine- and amphetamine-regulated transcript (CART), located in the ventrolateral division of the arcuate nucleus have recently been reported to contain the vesicular glutamate transporter 2 (VGLUT2), a marker for glutamatergic neurons, and the acetylcholine (ACh) synthesizing enzyme choline acetyltransferase (ChAT) as well as the vesicular ACh transporter (VAChT), supporting also a cholinergic phenotype. In the lateral hypothalamic area, hypocretin/orexin neurons express VGLUT1 or VGLUT2, but not GAD, whereas some melanin-concentrating hormone (MCH) cells contain GAD. These observations support the view that several classical transmitters, relatively neglected feeding transmitters candidates, are present in key neurons that regulate body weight and consequently may represent important orexigenic/anorexigenic mediators that convey information to other neurons within the hypothalamus as well as from the hypothalamus to other brain regions that participate in regulation of energy balance.

Presystemic signals in the control of thirst, salt appetite, and vasopressin secretion

Presystemic signals play an important role in the control of ingestive behavior by allowing animals to anticipate imminent physiological changes. The significance of such signals in the control of food intake has been amply demonstrated and is widely appreciated. Our recent experiments have revealed that presystemic signals also provide important early feedback when rats drink water or NaCl solution, before the ingested fluids are absorbed and influence cerebral osmoreceptors or cardiovascular baroreceptors. These early signals clearly affect vasopressin (VP) secretion and thirst. They relate either to the distension of the stomach and proximal small intestine (presumably mediated by local stretch receptors) or to the concentration of fluid that empties from the stomach into the small intestine (presumably mediated by visceral osmo- or Na +-receptors). Dehydrated dogs use functionally comparable signals from the oropharynx while drinking in order to inhibit both VP secretion and thirst. However, that system differs in several respects from the system in rats aside from the fact that the presystemic signals in rats are not oropharyngeal: in rodents, (a) separate early signals influence VP secretion and thirst, (b) early signals can provide both stimulation and inhibition of VP secretion and thirst, and (c) the early signals are associated with both the volume and concentration of ingested fluid. These presystemic signals also inhibit the intake of NaCl solution by rats with salt appetite.

Association of a missense mutation of the <i>MC4R</i> gene with growth traits in cattle (Brief report) (Assoziation einer Mutation im MC41 Gen mit Wachstumsmerkmalen beim Rind)

Abstract. Melanocortin-4 receptor (MC4R) is one of five G-protein-coupled receptors binding melanocortins that is implicated in the control of ingestive behavior and energy homeostasis. Mutations have been described in the human and mouse MC4R genes which are associated with obesity (YEO et al., 1998; HUSZAR et al., 1997). Moreover, a mutation in porcine MC4R is associated with economically important traits in the pig (KIM et al., 2000). The SNPs reported in bovine MC4R coding region were specific to breeds (VALLE et al., 2004; THUE et al., 2001; HAEGEMAN et al., 2001). In the present experiment over 95% of the coding region of MC4R were screened to detect the SNPs in the predominant cattle breeds of China. Association of a missense mutation of MC4R gene with growth traits was analyzed.

Sensory neurobiological analysis of neuropeptide modulation of meal size

Gerry Smith's emphasis on the meal as the functional unit of ingestion spurred experiments designed to (1) identify oral and postoral stimuli that affect meal size, and (2) identify peripheral and central neural mechanisms involved in the processing of sensory signals generated by these stimuli. His observations that gut–brain peptides can limit meal size were important in formulating the idea that neuropeptides involved in the control of food intake modulate the peripheral and central neural processing of meal-stimulated sensory signals. This focus on meal size continues to foster the development of hypotheses and the design of experiments that characterize the sites and modes of action of feeding modulatory neuropeptides. These investigations have focused attention on the gut–brain neuraxis as a critical sensory pathway in the control of ingestive behavior, and have revealed important integrative properties of peripheral and central neurons along this axis. The neuromodulatory function of peptides that alter food intake is supported by their ability to recruit the activation of neurons at multiple central nodes of the gut–brain axis and to affect the neural processing and behavioral potency of meal-related gastrointestinal signals important in the negative feedback control of meal size. This sensory neurobiological perspective may also be applied to determine whether feeding modulatory neuropeptides affect the neural and behavioral potency of oral positive feedback signals that promote ingestion.

Nociceptin/orphanin FQ acts as a functional antagonist of corticotropin-releasing factor to inhibit its anorectic effect

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP opioid receptor (previously referred to as ORL1 or OP4 receptor), exerts a variety of behavioral effects. N/OFQ as well as the synthetic NOP receptor agonist Ro 64-6198 have been reported to possess antistress properties and to elicit a pronounced hyperphagic effect in freely feeding rats. These findings have raised our interest to investigate possible interactions in the control of ingestive behavior between N/OFQ and corticotropin-releasing factor (CRF), which is well known to be a major mediator of stress and to possess anorectic properties. These studies have shown that intracerebroventricular injections of N/OFQ or of Ro 64-6198 reverse the anorectic action evoked by intracerebroventricular administration of CRF. The anti-anorectic effect of N/OFQ or Ro 64-6198 is antagonized by the selective NOP receptor antagonist [Nphe 1]N/OFQ(1-13)NH 2, providing evidence that it is mediated by this receptor. The effect occurs at doses that are not hyperphagic per se and is clearly selective versus the anorectic action of CRF since N/OFQ or Ro 64-6198 do not influence the anorectic effect of Escherichia coli lipopolysaccharide (LPS). Neither N/OFQ nor Ro 64-6198 shows affinity for CRF receptors, suggesting that NOP receptor agonists might act as functional antagonists of CRF with regard to its anorectic action. Microinjection studies have revealed that the bed nucleus of the stria terminalis (BNST) is highly sensitive to the anorectic action of CRF, as well as to the anti-anorectic action of N/OFQ; pretreatment with 0.025–0.25 μg/site of N/OFQ into the BNST blocked the anorectic action of 0.1 μg/site of CRF given in the same area. On the other hand, intra-BNST microinjection of 0.025–0.25 μg/site of N/OFQ did not modify basal food intake. Thus, the BNST may be the site where the functional antagonism between N/OFQ and CRF takes place. These findings raise interest for the N/OFQ-NOP receptor system as a pharmacological target to block the anorectic effect of CRF. In comparison to CRF receptor antagonists, NOP receptor agonists may have the advantage of not inhibiting the hypothalamic–pituitary–adrenal (HPA) axis.

Agouti-related protein: appetite or reward?

Agouti-related protein (AgRP) is an orexigenic peptide that acts as an antagonist of the melanocortin-3 and -4 receptors in the hypothalamus. Studies suggest that the melanocortin and opioid systems interact in the control of ingestive behavior. Also, AgRP has been shown to especially increase intake of a palatable diet. Given these observations, we wished to examine whether the effects of AgRP on ingestive behavior resemble those of opioids. AgRP was injected into the hypothalamic paraventricular nucleus in animals given a choice between a palatable sucrose solution and calorically dense chow. As a result of AgRP injection, animals increased intake of chow but not sucrose relative to controls, in contrast to what has been seen with opioid agonists. These results together with prior findings suggest that the primary effect of AgRP is to cause an increase in food intake to satisfy energy needs, though AgRP also has opioid-like effects, possibly due to melanocortin-opioid interactions.

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, 3.0 and 10.0 mg/kg) and d-fenfluramine (3.0 mg/kg). Ro 60-0175 produced a dose-dependent decrease in food intake. The effects of Ro 60-0175 (3.0 mg/kg) on the BSS were similar to the hypophagic effects of d-fenfluramine (3.0 mg/kg). In a second experiment, the specific effects on feeding produced by Ro 60-0175 (5.6 mg/kg) were attenuated by pretreatment with the selective 5-HT 2C receptor antagonist 6-chloro-5-methyl-1-[2(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl] indoline (SB 242084; 0.5 mg/kg). The 5-HT 1B/2C receptor agonist 1-( m-chlorophenyl)piperazine ( mCPP; 3 mg/kg) also produced a substantial decrease in food intake, which was attenuated by SB 242084 (0.5 mg/kg). A dose of the selective 5-HT 1B/1D antagonist 2′-methyl-4′(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-(5-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]amide (GR 127935; 3.0 mg/kg) that successfully attenuated the action of the 5-HT 1B agonist 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1 H-indole (RU 24969; 5.0 mg/kg) failed to attenuate mCPP-induced hypophagia. These data suggest that Ro 60-0175- and mCPP-induced hypophagia in mice are mediated via activation of 5-HT 2C receptors and that stimulation of 5-HT 1B receptors plays only a minor role in mCPP-induced hypophagia.