Dose-dependent Increase In Food Intake Research Articles

Posterodorsal Medial Amygdala Mediates Tail-Pinch Induced Food Intake in Female Rats.

Comfort eating during periods of stress is a common phenomenon observed in both animals and humans. However, the underlying mechanisms of stress‐induced food intake remain elusive. The amygdala plays a central role in higher‐order emotional processing and the posterodorsal subnucleus of the medial amygdala (MePD), in particular, is involved in food intake. Extra‐hypothalamic corticotrophin‐releasing factor (CRF) is well recognised for mediating behavioural responses to stress. To explore the possible role of amygdala CRF receptor activation in stress‐induced food intake, we evaluated whether a stressor such as tail‐pinch, which reliably induces food intake, would fail to do so in animals bearing bilateral neurotoxic lesions of the MePD. Our results showed that ibotenic acid induced lesions of the MePD markedly reduced tail‐pinch induced food intake in ovariectomised, 17β‐oestradiol replaced rats. In addition, intra‐MePD (right side only) administration of CRF (0.002 or 0.02 ng) via chronically implanted cannulae resulted in a dose‐dependent increase in food intake, although higher doses of 0.2 and 2 ng CRF had less effect, producing a bell shaped curve. Furthermore, intra‐MePD (bilateral) administration of the CRF receptor antagonist, astressin (0.3 μg per side) effectively blocked tail‐pinch induced food intake. These data suggest that the MePD is involved in stress‐induced food intake and that the amygdala CRF system may be a mediator of comfort eating.

Selective serotonin receptor stimulation of the medial nucleus accumbens differentially affects appetitive motivation for food on a progressive ratio schedule of reinforcement

Previously, we reported that stimulation of selective serotonin (5-HT) receptor subtypes in the nucleus accumbens shell differentially affected consumption of freely available food. Specifically, activation of 5-HT6 receptors caused a dose-dependent increase in food intake, while the stimulation of 5-HT1/7 receptor subtypes decreased feeding [34]. The current experiments tested whether similar pharmacological activation of nucleus accumbens serotonin receptors would also affect appetitive motivation, as measured by the amount of effort non-deprived rats exerted to earn sugar reinforcement. Rats were trained to lever press for sugar pellets on a progressive ratio 2 schedule of reinforcement. Across multiple treatment days, three separate groups (N=8–10) received bilateral infusions of the 5-HT6 agonist EMD 386088 (at 0.0, 1.0 and 4.0μg/0.5μl/side), the 5-HT1/7 agonist 5-CT (at 0, 0.5, 1.0, or 4.0μg/0.5μl/side), or the 5-HT2C agonist RO 60-0175 fumarate (at 0, 2.0, or 5.0μg/0.5μl/side) into the anterior medial nucleus accumbens prior to a 1-h progressive ratio session. Stimulation of 5-HT6 receptors caused a dose-dependent increase in motivation as assessed by break point, reinforcers earned, and total active lever presses. Stimulation of 5-HT1/7 receptors increased lever pressing at the 0.5μg dose of 5-CT, but inhibited lever presses and break point at 4.0μg/side. Injection of the 5-HT2C agonist had no effect on motivation within the task. Collectively, these experiments suggest that, in addition to their role in modulating food consumption, nucleus accumbens 5-HT6 and 5-HT1/7 receptors also differentially regulate the appetitive components of food-directed motivation.

AICAR and Compound C regulate food intake independently of AMP-activated protein kinase in lines of chickens selected for high or low body weight

AMP-activated protein kinase (AMPK) functions to maintain cellular and body energy balance. Our aim was to investigate the effect of intracerebroventricular (ICV) administration of AMPK stimulator AICAR and AMPK inhibitor Compound C on food intake in lines of chickens that had undergone long-term selection from a common founder population for high (HWS) or low (LWS) body weight. AICAR caused a quadratic dose-dependent decrease in food intake in LWS but not HWS chicks. Compound C caused a quadratic dose-dependent increase in food intake in HWS but not in LWS chicks. Key aspects of the AMPK pathway, including upstream kinases mRNA expression, AMPK subunit α mRNA expression and phosphorylation, and a downstream target acetyl CoA carboxylase (ACC) phosphorylation were not affected by either AICAR or Compound C in either line. The exception was a significant inhibitory effect of AICAR on ACC phosphorylation ratio due to increased total ACC protein content without changing phosphorylated ACC protein levels. Thus, the anorexigenic effect of AICAR in LWS chicks and orexigenic effect of Compound C in HWS chicks resulted from activation or inhibition of other kinase pathways separate from AMPK. These results suggest genetic variation in feeding response for central AICAR and Compound C in chickens, which may contribute to the different body weights between the HWS and LWS lines.

Genetic selection for body weight in chickens has altered responses of the brain's AMPK system to food intake regulation effect of ghrelin, but not obestatin

The effects of ghrelin and obestatin regulation of food intake are different in mammals and chickens. We investigated central effects of ghrelin and obestatin in lines of chickens selected 50 generations for high (HWS) or low (LWS) body weight. We hypothesized that the effect of ghrelin and obestatin on food intake in 5-day-old chicks is mediated by the AMP-activated protein kinase (AMPK) system and selection for body weight alters the brain's response to ghrelin and obestatin by changing the neuronal AMPK system. Although intracerebroventricular (ICV) ghrelin injection decreased food intake in both lines, the threshold for the anorexigenic effect of central ghrelin was lower in LWS than HWS chicks. Obestatin caused a linear dose-dependent increase in food intake in HWS but not LWS chicks. ICV injection of 0.4 nmol ghrelin inhibited hypothalamic AMPK related gene expression and phosphorylation of AMPK α and acetyl-CoA carboxylase (ACC) with the magnitude of inhibition different in the two lines. In contrast, ICV injection of 4 nmol obestatin did not affect mRNA expression of AMPK system or phosphorylation of AMPK and ACC in either line. These data support the premise of a lower threshold for anorexigenic effect of central ghrelin in LWS than HWS chicks, and this difference may be associated with differential hypothalamic AMPK signaling. Additionally, the hypothalamic mRNA level of ghrelin was significantly higher in LWS than HWS, which may have also contributed to the different threshold response to ghrelin in these two lines. The expression of the ghrelin receptor was also higher in the LWS line, but not until 56 days of age. In summary, selection for body weight has resulted in differences in the central ghrelin and obestatin system, and an altered brain AMPK system may contribute to the different neuronal response to ghrelin, but not obestatin.

Substance P as a Novel Anti-obesity Target

Substance P (SP) is an 11-amino acid peptide that belongs to the tachykinin family of peptides. SP acts in the brain and in the periphery as a neuropeptide, neurotransmitter, and hormone affecting diverse physiologic pathways, mainly via its high-affinity neurokinin-1 receptor (NK-1R). Its presence in the hypothalamus and other areas of the brain that regulate feeding as well as in the stomach and small intestine prompted us to investigate its role on appetite control and energy balance. CJ 012,255 (CJ), a SP antagonist that binds to NK-1R, was injected into lean, diet-induced obese (DIO), and genetically obese (ob/ob) mice, and its effects on body weight, adiposity, and insulin sensitivity were investigated. CJ administration prevented weight gain and accumulation of fat after 2 weeks of high-fat feeding, whereas similar CJ treatment in obese mice (following 3 months of high-fat diet) resulted in weight loss, reduction in adiposity, and improvement of insulin sensitivity, in part because of inhibition of food intake. The effects of SP in the control of energy balance are, at least in part, leptin independent because CJ treatment was also effective in leptin-deficient mice. Peripheral SP administration resulted in a mild, dose-dependent increase in food intake, evident 3 hours post-SP injection. CJ reduces appetite and promotes weight loss in mice. We speculate that NK-1R antagonists, already tested in clinical trials for various diseases, may represent a potential target against obesity.

This Month in Gastroenterology

This Month in Gastroenterology

Association of Genetic Variation Within UBL5 with Phenotypes of Metabolic Syndrome

The BEACON gene was initially identified using the differential display polymerase chain reaction on hypothalamic mRNA samples collected from lean and obese Psammomys obesus, a polygenic animal model of obesity. Hypothalamic BEACON gene expression was positively correlated with percentage of body fat, and intracerebroventricular infusion of the Beacon protein resulted in a dose-dependent increase in food intake and body weight. The human homolog of BEACON, UBL5, is located on chromosome 19p in a region previously linked to quantitative traits related to obesity. Our previous studies showed a statistically significant association between UBL5 sequence variation and several obesity- and diabetes-related quantitative physiological measures in Asian Indian and Micronesian cohorts. Here we undertake a replication study in a Mexican American cohort where the original linkage signal was first detected. We exhaustively resequenced the complete gene plus the putative promoter region for genetic variation in 55 individuals and identified five single nucleotide polymorphisms (SNPs), one of which was novel. These SNPs were genotyped in a Mexican American cohort of 900 individuals from 40 families. Using a quantitative trait linkage disequilibrium test, we found significant associations between UBL5 genetic variants and waist-to-hip ratio (p = 0.027), and the circulating concentrations of insulin (p = 0.018) and total cholesterol (p = 0.023) in fasted individuals. These data are consistent with our earlier published studies and further support a functional role for the UBL5 gene in influencing physiological traits that underpin the development of metabolic syndrome.

Serotonin Receptor Blockade Increases Food Intake and Body Weight after Total Gastrectomy in Rats

Background. Total gastrectomy often results in early satiety and loss of body weight. Serotonin inhibits food intake, and postprandial serotonin release is increased after total gastrectomy. Serotonin might contribute to early satiety and loss of body weight after total gastrectomy. Methods and materials. Food intake and body weight were investigated with an automated recording system in gastrectomized rats 1–12 months postoperatively. Rats were treated with metergoline, a 5-hydroxytryptamine (5-HT) 1/2 receptor antagonist, two different 5-HT 3 receptor antagonists, a combination of metergoline and devazepide, a cholecystokinin (CCK) a receptor antagonist, or vehicle. In addition, metergoline or vehicle was applied continuously by an intraperitoneal osmotic minipump for 7, 28, or 84 days after total gastrectomy. Results. Metergoline treatment resulted in a dose-dependent increase in food intake in gastrectomized rats. 5-HT 3 receptor antagonist treatment had no effect, and devazepide in addition to metergoline did not further stimulate food intake. Metergoline increased food intake at 1, 3, and 6 months postoperatively by up to 45% (24-h cumulative food intake [FI], 6 months: vehicle 3.83 ± 0.10, metergoline 5.52 ± 0.15 g/100 g body weight (BW), P < 0.0001). Chronic metergoline treatment for 7, 28, or 84 days significantly increased food intake after total gastrectomy compared to vehicle treatment (FI 7 days: vehicle 30.83 ± 0.71, metergoline 36.27 ± 0.85 g/100 g BW; P < 0.0002; average weekly FI during 28 days; vehicle 31.23 ± 0.22, metergoline 36.83 ± 0.33 g/100 g BW, P < 0.0001; average weekly FI during 84 days: vehicle 33.02 ± 0.59, metergoline 35.07 ± 0.48 g/100g BW, P < 0.008), and there was a significant body weight increase compared to vehicle treatment (7 days: ΔBW vehicle −0.7 ± 1.2 g vs ΔBW metergoline 9.0 ± 2.1 g, P < 0.001; 28 days: ΔBW vehicle 0.3 ± 2.2 vs ΔBW metergoline 13.0 ± 2.3, P < 0.001; 84 days: ΔBW vehicle 25.7 ± 10.2 vs ΔBW metergoline 49.5 ± 7.2, P < 0.04). Treatment for 84 days resulted in a significant body weight gain, while vehicle treatment had no effect (vehicle: 438 ± 11 g vs 464 ± 12 g, P < 0.2, n.s.; metergoline: 448 ± 9 g vs 498 ± 10 g, P < 0.007). Conclusions. Inhibition of food intake by serotonin might contribute to early satiety and loss of body weight after total gastrectomy.

GABAergic control of food intake in the meat-type chickens

This study examined the effects of intracerebroventricular injections of γ-aminobutyric acid (GABA) agonists on short-term food intake in meat-type cockerels. In Experiment 1, birds were injected with various doses of muscimol, a GABA A agonist. In Experiment 2, the birds received bicuculline, a GABA A antagonist, prior to injection of muscimol. In Experiment 3, the effect of varying doses of baclofen, a GABA B agonist, on food intake was determined. The intracerebroventricular injection of muscimol caused a dose-dependent increase in food intake. This effect was significantly attenuated by pretreatment with bicuculline. Food intake was not affected by the intracerebroventricular injection of baclofen. These results suggest that GABA acts within the brain of broilers at a GABA A, but not GABA B, receptor to increase voluntary food intake.

Tonic inhibition of food intake during inactive phase is reversed by the injection of the melanocortin receptor antagonist into the paraventricular nucleus of the hypothalamus and central amygdala of the rat

Melanocortins inhibit food intake and melanocortin 4 receptor (MC 4R) antagonists stimulate feeding behaviour. These effects may occur due to stimulation or blockade of MC 4 receptors in the hypothalamus. To test the validity of this hypothesis, a cyclic peptide, the MC 4R selective antagonist HS014 (20, 100 and 500 pmol), or vehicle, was injected unilaterally into the paraventricular nucleus of the hypothalamus (PVN). As MC receptors are expressed also in extrahypothalamic sites involved in the regulation of feeding behaviour, HS014 was injected bilaterally into the vicinity of the central nucleus of the amygdala (CA) and the nucleus accumbens region (Acc). All doses of HS014 induced a dose-dependent increase in food intake when injected into the PVN. Intra-amygdalar injections of HS014 (50 and 250 pmol/side) also stimulated food intake, whereas a 10-pmol dose was inactive. Local microinjections of HS014 into the Acc failed to stimulate feeding. These data suggest that endogenous melanocortin receptor agonists exert a tonic inhibitory influence on food consumption by stimulating MC 4 receptors in the hypothalamus and amygdala.

Beacon: a novel gene involved in the regulation of energy balance.

The hypothalamus plays a major role in the control of energy balance via the coordination of several neuropeptides and their receptors. We used a unique polygenic animal model of obesity, Psammomys obesus, and performed differential display polymerase chain reaction on hypothalamic mRNA samples to identify novel genes involved in obesity. In this study, we describe a novel gene that encodes a small protein we have termed "beacon." Beacon mRNA gene expression in the hypothalamus was positively correlated with percentage of body fat. Intracerebroventricular infusion of beacon resulted in a dose-dependent increase in food intake and body weight and an increase in hypothalamic expression of neuropeptide Y (NPY). Simultaneous infusion of beacon and NPY significantly potentiated the orexigenic response and resulted in rapid body weight gain. These data suggest a role for beacon in the regulation of energy balance and body weight homeostasis that may be mediated, at least in part, through the NPY pathway.

Ghrelin induces adiposity in rodents.

The discovery of the peptide hormone ghrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor, yielded the surprising result that the principal site of ghrelin synthesis is the stomach and not the hypothalamus. Although ghrelin is likely to regulate pituitary growth hormone (GH) secretion along with GH-releasing hormone and somatostatin, GHS receptors have also been identified on hypothalamic neurons and in the brainstem. Apart from potential paracrine effects, ghrelin may thus offer an endocrine link between stomach, hypothalamus and pituitary, suggesting an involvement in regulation of energy balance. Here we show that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats. Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight. Rat serum ghrelin concentrations were increased by fasting and were reduced by re-feeding or oral glucose administration, but not by water ingestion. We propose that ghrelin, in addition to its role in regulating GH secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary.

Regulation of food intake by neuropeptide Y in goldfish.

In mammals, neuropeptide Y (NPY) is a potent orexigenic factor. In the present study, third brain ventricle (intracerebroventricular) injection of goldfish NPY (gNPY) caused a dose-dependent increase in food intake in goldfish, and intracerebroventricular administration of NPY Y1-receptor antagonist BIBP-3226 decreased food intake; the actions of gNPY were blocked by simultaneous injection of BIBP-3226. Goldfish maintained on a daily scheduled feeding regimen display an increase in NPY mRNA levels in the telencephalon-preoptic area and hypothalamus shortly before feeding; however, a decrease occured in optic tectum-thalamus. In both fed and unfed fish, brain NPY mRNA levels decreased after scheduled feeding. Restriction in daily food ration intake for 1 wk or food deprivation for 72 h resulted in increased brain NPY mRNA levels. Results from these studies demonstrate that NPY is a physiological brain signal involved in feeding behavior in goldfish, mediating its effects, at least in part, through Y1-like receptors in the brain.

Discovery of a novel superpotent and selective melanocortin-4 receptor antagonist (HS024): evaluation in vitro and in vivo.

Several novel cyclic MSH analogs were synthesized, and their binding properties were tested on cells transiently expressing the human melanocortin-1 (MC1), MC3, MC4, and MC5 receptors. We discovered a novel substance (HS024) that showed about 20-fold selectivity and very high affinity (Ki = 0.29 nM) for the MC4 receptor. HS024 (cyclic [AcCys3,Nle4,Arg5,D-Nal7,Cys-NH2(11)]alpha-MSH-(3-11)) has a 29-membered atom ring structure that includes an Arg in position 5. HS024 was found to antagonize an alphaMSH-induced cAMP response in cells expressing the human MC1, MC3, MC4, and MC5 receptor DNAs. HS024 also caused a dose-dependent increase in food intake, with a maximum response (4-fold increase) at a 1-nmol dose injected intracerebroventricularly in free feeding rats. We also tested SHU9119, a previously described nonselective MC receptor antagonist, and found HS024 and SHU9119 to have similar potencies for increasing food intake, although SHU9119 appeared to induce more serious side-effects. HS024 increased the food intake of free feeding rats to levels comparable to those in food-deprived rats, indicating that blockade of the MC4 receptor is a highly effective way to increase feeding. Moreover, we tested the effects of intracerebroventricular injections of HS024 in elevated plus-maze and open-field experiments on rats. In these tests, HS024 did not appear to affect emotionality or locomotor activity, suggesting that the MC4 receptor does not mediate the anxiogenic-like and locomotor effects related to the melanocortic peptides.

Dopamine receptor sensitive effect of dizocilpine on feeding behaviour

The effect of intracerebroventricular administration of dizocilpine on feeding behaviour and adrenal corticrotropic hormone (ACTH)-induced anorexia in elevated plus maze was examined. Dizocilpine (10, 20 and 40 nmol/rat, i.c.v.) showed a dose-dependent increase in food intake in 16 h food deprived rats. Dopamine receptor antagonists such as SCH 23390 (0.25 and 0.5 mg/kg, i.p.), pimozide (0.5 and 1 mg/kg, i.p.) and haloperidol (0.25 and 0.5 mg/kg, i.p.) dose-dependently blocked dizocilpine (40 nmol)-induced potentiation of food intake. Brain dopamine depletion by pretreatment with reserpine (5 mg/kg, i.p.) and alpha-methyl- p-tyrosine (200 mg/kg, i.p.) decreased food intake in rats. Similarly, pretreatment with reserpine and alpha-methyl- p-tyrosine (AMPT) reversed the hyperphagic effect of dizocilpine (20 and 40 nmol). Intracerebroventricular administration of ACTH (5 μg/rat) produced significant diminution of feeding duration and increased tasting latency and feeding latency in elevated plus maze which was reversed by dizocilpine (40 nmol). SCH 23390 (0.25 mg/kg), pimozide (0.5 mg/kg) and haloperidol (0.25 mg/kg) reversed the effect of dizocilpine on ACTH-induced behaviours in elevated plus maze. The present observations support and extend the hypothesis that endogenous excitatory aminoacids (EAAs) play a role in the control of food intake. Further, dizocilpine-induced hyperphagia and dizocilpine-induced reversal of ACTH effect on feeding behaviour in elevated plus maze involve DAergic mediation.

Effect of K + channel modulation on mouse feeding behaviour

The K + channel antagonists, glucose (100 μg per mouse i.c.v.), tetraethylammonium (1 μg per mouse i.c.v.) and apamin (1 ng per mouse i.c.v.), reduced food intake of mice comparably to the two anorectic drugs, amphetamine (10 μg per mouse i.c.v.) and cocaine (50 μg per mouse i.c.v.). Conversely, the K + channel openers, minoxidil (5 μg per mouse i.c.v.) and pinacidil (10 μg per mouse i.c.v.), elicited an orectic effect of the same intensity as that induced by 2-deoxyglucose (200 μg per mouse i.c.v.), aurothioglucose (200 μg per mouse i.c.v.) and neuropeptide Y (0.5 μg per mouse i.c.v.). The antisense oligodeoxyribonucleotide (1–3 nmol per injection) to mKv1.1 gene produced, at 72 h, a dose-dependent increase in food intake. A quantitative reverse transcription-polymerase chain reaction (RT-PCR) study demonstrated a reduction in cerebral mRNA levels only in the antisense oligodeoxyribonucleotide-treated group, indicating the absence of a sequence-independent action. Mice receiving the K + channel modulators or antisense oligodeoxyribonucleotide had unmodified motor coordination and inspection activity as revealed, respectively, by the rotarod and hole-board tests. The integrity and functionality of central K + channels appears, therefore, to be fundamental in the regulation of food intake by mice.

The effect of central administration of prolactin on food intake in virgin female rats is dose-dependent, occurs in the absence of ovarian hormones and the latency to onset varies with feeding regimen

Lactation in mammals is characterized by a marked hyperphagia and significantly elevated levels of prolactin (PRL). Several recent experiments in our laboratory have provided evidence for a causal relationship between PRL and hyperphagia. The present series of studies revealed that PRL injected intracerebroventricularly (i.c.v.) twice daily for ten days to free feeding virgin female rats produced a dose-dependent increase in food intake without disrupting vaginal cyclicity, that the hyperphagic effect of centrally administered PRL was not dependent on the presence of ovarian hormones, that it did not selectively potentiate feeding during the light or dark phase of the daily light cycle and that the latency of the feeding response to i.c.v. PRL administration was shorter in food restricted animals. Taken together, these results support the idea that PRL acts centrally to potentiate food intake.

Central effects of monosodium glutamate on feeding behavior in adult long-evans rats

Monosodium glutamate (MSG) is known as a neurotoxic molecule when injected neonatally in rats, where it produces a marked decrease in food intake and an increase in adipose tissue mass. But, in adult rats subcutaneous injections of MSG produce a small, dose-dependent increase in food intake. It is not known if this action is centrally or systemically mediated. Therefore, the feeding pattern of adult rats injected intracerebroventricularly with MSG was measured. Seven days after installation of a cannula in the right lateral ventricle, rats were injected either with artificial cerebrospinal fluid or twice with 3 mg/brain MSG within a 3-day interval. The feeding pattern was recorded via a complete computerized system during 24 h. Feeding behavior was significantly modified by MSG treatments. These effects were observed immediately after drug injections, that is, upon the first meal, as well as during the 24 h that followed. For the first meal, modifications in meal size (+285%; p = 0.0001), meal duration (×10; p = 0.0005), postmeal interval (×4; p = 0.0005), and the satiety ratio (− 50%; p = 0.01) were observed. During the 24-h postinjection period, modifications in meal number (−3; p = 0.0007), total amount of food eaten (+21%; p = 0.007), time spent eating (+40%; p = 0.007), meal duration (+53%; p = 0.005), and meal size (+44%; p = 0.01) were noted. When the two MSG injections were compared, differences were also noted. For the first meal, postmeal interval (−50%; p < 0.005) and satiety ratio (−50%; p < 0.005) were decreased after the second injection. During the 24-h postinjection period, meal duration (−50%; p < 0.05) and time spent to eat (−25%; p < 0.05) were also decreased. This study showed that MSG must be considered a potent stimulant of food intake when administered through a central route. This effect was more powerful than that observed with systemic MSG injection, even at several thousand-fold smaller doses. This stimulation of food intake might be mediated by the stimulatory effect of MSG on release of neuromodulators present in the circumventricular nuclei such as the arcuate nucleus. A small neurotoxic action of MSG is possible when the injections are repeated.

Induction of food intake by a GABAergic mechanism in the turkey

The effect of GABAergic influences on food and water intake in Large White turkeys was investigated. In Experiment 1, food and water intake were monitored in hens injected intracerebroventricularly (ICV) with varying doses of muscimol, a GABA agonist. In Experiment 2, hens were pretreated with ICV injections of picrotoxin, a GABA antagonist, prior to the injection of muscimol. In Experiment 3, the effect of ICV injections of muscimol on water intake was determined in hens not allowed access to food. The ICV injection of muscimol caused a dose-dependent increase in food intake with 75 nmole being the most efficacious dose. Water intake was stimulated following the injection of muscimol when food and water were available ad lib. However, water intake was not affected by the ICV injection of muscimol if food was not simultaneously available, indicating that the increased water intake was a result of increased food intake. The effect of muscimol on food intake was significantly attenuated by pretreatment with picrotoxin. It appears, therefore, that GABA acts within the brain of the turkey to increase food, but not water, intake.

The involvement of 5‐hydroxytryptaminergic and dopaminergic mechanisms in the eating induced by buspirone, gepirone and ipsapirone

1. The roles of 5-hydroxytryptamine (5-HT) and dopamine systems in mediating the increased feeding induced by buspirone, gepirone and ipsapirone were investigated. 2. All three compounds induced dose-dependent increases in food intake when administered subcutaneously to free feeding rats. Buspirone was effective over a narrower dose range than either gepirone or ipsapirone, and the maximal effect observed was smaller than the effects elicited by gepirone and ipsapirone. 3. Depletion of brain 5-HT with parachlorophenylalanine (PCPA) prevented the effects of equi-effective doses of gepirone (2.5 mg kg-1) and ipsapirone (2.5 mg kg-1), but failed to prevent buspirone (1 mg kg-1)-induced eating. Thus buspirone does not appear to interact with 5-HT systems to elicit feeding. 4. Gepirone (0.2 micrograms) and ipsapirone (0.04 and 0.2 micrograms) increased food intake when injected into the dorsal raphé nucleus (DRN), presumably by inhibiting the activity of DRN 5-hydroxytryptaminergic afferents. Buspirone (0.04-5 micrograms) was ineffective when injected into the DRN. 5. Pretreatment with haloperidol (0.1 mg kg-1, 30 min) significantly attenuated the effects of equi-effective doses of buspirone, gepirone and ipsapirone, indicating that these drugs interact with dopaminergic systems to increase feeding. 6. Previously it has been shown that each of these drugs increases striatal dopamine activity. Increased dopaminergic neurotransmission in the striatum induces a general behavioural activation, which under certain conditions facilitates feeding. It is possible that this mechanism underlies the behavioural effects of buspirone, gepirone and ipsapirone. The effects of gepirone and ipsapirone probably involve an indirect action to inhibit the activity of DRN 5-hydroxytryptaminergic afferents, whereas buspirone interacts directly with dopaminergic systems.