Neuropeptide Y: A potent inducer of consummatory behavior in rats

Neuropeptide Y (NPY) is a 36 amino acid peptide with potent cardiovascular effects. In the present study, intraventricular injection of NPY was shown to markedly stimulate feeding and drinking during the illuminated period of the light/dark cycle, a time when rats ingest small amounts of food. It also enhanced nocturnal food and water intake following a 24 hour period of food deprivation and during nocturnal feeding. The NPY induction of food intake was suppressed by the opiate antagonist, naloxone, and by the dopamine antagonist, haloperidol. Phentolamine, an alpha adrenergic antagonist, failed to suppress NPY-induced feeding. Based on the maximum quantity of food which was ingested following central administration of NPY, this peptide appears to represent one of the most potent stimulators of feeding yet to be described.     

Oxytocin, water intake, and food sodium availability in male rats

This study examined the effect of subcutaneous administration of the neurohormone oxytocin on water intake of ad lib-fed (with or without sodium availability in the diet) and food-deprived animals. Results of the first experiment showed that oxytocin increased water intake and urine excretion in food-deprived but not in ad lib-fed animals. However, oxytocin treatment did not modify the reduced water "balance" (fluid intake minus urine volume) resulting from food deprivation or the daily food intake (Experiment 1). The dose-dependent polydipsic effect of oxytocin on food-deprived rats was always preceded by an increase in sodium and fluid urine excretion (Experiment 2). Oxytocin also increased the water intake of animals fed ad lib with a low sodium diet (Experiment 3). These results suggest that the effect of oxytocin on water intake is dependent on the presence or absence of sodium in the diet and that the excretion of sodium is the main mechanism of oxytocinergic polydipsia in food-deprived male rats.     

Both cyclooxygenase and lipoxygenase inhibitor partially restore the anorexia by interleukin-1 beta.

Since the peripheral prostaglandin synthetizing system may at least partly involved in the anorexia that follows central interleukin-1 beta (IL-1) administration, this study was undertaken to investigate the effect of ibuprofen (ip), selective cyclooxygenase blocker and AA 861, selective lipoxygenase inhibitor, on changes of food and water intake by a single injection of IL-1 (2 micrograms/rat, ip). We demonstrated that food and water intake were suppressed by peripheral administration of IL-1. Throughout the entire observation periods, suppressed food intake was partially restored to control levels by ibuprofen, while water intake completely restored. In addition, no significant differences about water/food intake were observed in the IL-1 + ibuprofen-treated groups, respectively. In the next experiment, IL-1 induced anorexia was also partially restored to the control level following pretreatment with AA 861. These results may suggest that other mechanism including lipoxygenase blocker besides prostaglandin production may be involved in IL-1 induced anorexia.     

Bombesin stimulates insulin secretion and reduces food intake in the baboon

Baboons received a 5-minute intravenous infusion of either saline or bombesin (BBS; 1-4 micrograms/kg) following 3 1/2 or 16 1/2 hours of food deprivation and were then allowed to eat for 30 minutes. Plasma insulin was significantly elevated following five minutes of BBS infusion, but there was no change of plasma glucose over the same interval. Bombesin infusion resulted in a dose-dependent decrease of food intake that was independent of deprivation time. Plasma insulin levels following the 30-minute meal were significantly depressed after BBS infusions such that there was essentially no change of plasma insulin over the duration of the meal, even though the baboons did not totally suppress their food intake. Following 3 1/2 hours food deprivation, BBS suppressed the post-prandial rise of plasma glucose in a dose-dependent manner. The results provide further evidence that BBS and/or structurally-related peptides are involved in the regulation of feeding and metabolism.     

Influence of the subfornical organ on meal-associated drinking in rats

A lesion of the subfornical organ (SFO) may disrupt drinking after a meal of dry chow as it does drinking after intragastric administration of hypertonic saline. Food and water intakes of SFO-lesioned (SFOX) and sham-lesioned rats were measured during 90-min tests following various lengths of food deprivation. During the tests, all rats began eating before they began drinking. After 20-24 h of food deprivation, latency to begin drinking after eating had started was longer for SFOX than for sham-lesioned rats. Plasma osmolality was elevated by 2-3% in both lesion groups at 12 min, the latency for sham-lesioned rats to drink, but SFOX rats nevertheless continued eating and delayed drinking. Eating after shorter 4-h food deprivations and ad libitum feeding produced more variable drinking latencies and less consistent effects of SFO lesion. During 24 h of water deprivation, SFO lesion had no effect on the suppression of food intake and did not affect food or water intakes during the first 2 h of subsequent rehydration. These findings indicate that the SFO is involved in initiating water intake during eating and in determining drinking patterns and the amount of water ingested during a meal.     

A sex difference in the effect of CCK-8 on food and water intake in obese (ob/ob) and lean (+/+) mice

Male and female ob/ob and +/+ mice were tested with CCK-8 (1, 2, 4 and 8 micrograms/kg) administered 15 min prior to 30-min access to solid food after 17.5 hr food deprivation and 15 min prior to 30-min access to water after 17.5 hr water deprivation. The threshold dose for suppressing 30-min food intake was 2 micrograms/kg for all mice. Larger doses of CCK-8 inhibited food intake in male obese and lean mice in a linear fashion. The dose-response relationship for female mice, however, was not linear: lean females failed to suppress food intake following 4 or 8 micrograms/kg and obese females did not suppress food intake at 4 micrograms/kg. There was also a sex difference in the effect on water intake. No dose of CCK-8 changed water intake in lean males and only the 8 micrograms/kg dose decreased water intake in obese males. In contrast CCK-8 (1, 4 and 8 micrograms/kg) increased water intake in obese females, CCK-8 (1 and 8 micrograms/kg) increased water intake in lean females and no dose of CCK-8 decreased water intake in females. These data demonstrate significant sex differences in the effect of CCK-8 on food and water intake in mice.     

Effects of fourth ventricle bombesin injection on meal-related parameters and grooming behavior.

Injections of bombesin (BN) into the vicinity of the caudal brainstem suppress food intake in rats. In the present study, the food intake parameters [meal size (MS), intermeal interval (IMI), satiety ratio (SR)] affected by 4th ventricle BN injections were determined. Following a 15-h food deprivation, rats were administered 4th ventricle injections of saline (0.15 M) and BN in doses of 1, 5, 10, and 20 ng BN, and were then given access to sweetened milk. The animals' behaviors (feeding, resting, grooming, exploring) were scored every one min and milk intake every five min for 60 min following the injections. Fourth ventricle injections of 5 ng BN and greater reliably suppressed milk. intake. This reduction was reflected in a significant reduction in the MS. The IMI was not affected. As a result, the SR (IMI2/MS1), which is thought to represent the satiating property of food, was reliably greater following BN than following saline administration. The reduced food intake was accompanied by a significant increase in grooming behavior and a corresponding decrease in exploring. The amount of time spent resting (inactive) was similar following saline and all but the highest dose of BN. To demonstrate that the behavioral effects of BN were mediated by specific caudal brainstem BN receptors, 4th ventricle injections of [D-Phe12,Leu14]BN, a BN receptor antagonist, or saline preceded the 4th ventricle injection of 5 ng BN. Pretreatment with [D-Phe12,Leu14]BN reliably blocked the effects of BN on food intake and grooming.     

Atrial natriuretic peptide inhibits water and sodium intake in rabbits

The effect of atrial natriuretic peptide (ANP) on water and sodium intake was investigated in wild rabbits, a species which does not drink water following i.c.v. or i.v. administration of angiotensin II but develops sodium appetite following i.c.v. infusion of angiotensin II. ANP was given during or after depletion of extracellular fluid volume: hemorrhage, fluid deprivation and administration of furosemide. Systemically administered ANP reduced the water, but not the sodium intake of wild rabbits. I.c.v. administration of ANP inhibited both water and sodium intake. The suppression of thirst following both i.v. and i.c.v. administration of ANP indicates that inhibition of the effect of angiotensin II is not the exclusive mechanism and the circumventricular organs are probably not the exclusive sites of action for ANP. The inhibition of sodium appetite in wild rabbits was consistent with earlier proposals that ANP acts through the inhibition of the effects of angiotensin II. Reduction of food intake coincident with administration of ANP was also noted, but dose-dependent decrease was not observed.     

Interoceptive "satiety" signals produced by leptin and CCK

The present studies assessed the extent to which the adiposity signal leptin and the brain-gut hormone cholecystokinin (CCK), administered alone or in combination, give rise to interoceptive sensory cues like those that are produced by a low (1h) level of food deprivation. Rats were trained with cues arising from 1 to 24-h food deprivation as discriminative stimuli. For one group, 24-h food deprivation predicted the delivery of sucrose pellets, whereas 1-h food deprivation did not. Another group received the reversed deprivation level-sucrose contingency. After asymptotic performance was achieved, the effects of leptin and CCK on food intake and on discrimination performance were tested under 24-h food deprivation. In Experiment 1a, leptin administered into the third cerebroventricle (i3vt) at 3.5 or 7.0 microg doses had little effect, compared to saline on food intake or discriminative responding. In Experiment 1b, leptin (7.0 microg, i3vt) combined with CCK-8 (2 microg/kg, i.p.) reduced food intake significantly, but the findings indicated that CCK-8 alone produces interoceptive discriminative cues more like those produced by 1- than 24-h food deprivation. Experiment 2a tested rats with i.p. leptin (0.3 and 0.5mg/kg). Although neither dose suppressed intake, the 0.3mg/kg dose produced interoceptive cues like 1-h food deprivation. Experiment 2b tested two doses of CCK-8 (2 and 4 mg/kg, i.p.) and found significant intake suppression and generalization of discrimination with both doses of CCK-8. These findings suggest a role for both leptin and CCK in the production of sensory consequences that correspond to "satiety".     

Stress induced differential intake of various diets and water by rat: the role of the opiate system

The purpose of this study was to explore the effect of acute mild stress (12–48 hour food and water deprivation) and acute severe stress (12 hour food and water deprivation followed by 10 min swim in water at 4°) on the intake of different isocaloric dietary regimes. Each group of experimental animals was given only one particular diet. Rats subjected to mild stress showed very little preference of dietary regimes. When the food intake was measured during 3 hour period, following 48 hours of fasting, animals showed 2 to 3 fold increase in the food and water intake but no particular dietary preference. However, when rats were subjected to severe stress, there was an increase in the food intake of 154% (control diet); 174% (high-carbohydrate diet); 310% (high protein diet) and 423% (high fat diet) compared to animals subjected to mild stress. In terms of the absolute quantity of food, the animals subjected to severe stress ate more high-fat diet than any other diet; the consumption of high fat diet was 142% more than high-protein diet, 180% more than control diet and 258% more than high carbohydrate diet. Animals subjected to severe stress and given high-carbohydrate and high fat diet also showed 80% increase in the water intake. Prior administration of naloxone (1 mg/kg body weight, i.p.) reduced the stress induced increase in the intake of food and water. Naloxone inhibited the intake of high-fat diet more than any other diet. The ability of naloxone to block the increase in the intake of high-fat diet, and the reported increase in the concentration of β-endorphin in the different regions of brain of the animals subjected to the cold swim, suggest that endogenous opioid system in body is activated during stress. An activation of the endogenous opioid system leads to a preferential increase in the intake of palatable foods.     

Glucagon-like peptide-1 receptor agonists suppress water intake independent of effects on food intake

Glucagon-like peptide-1 (GLP-1) is produced by and released from the small intestine following ingestion of nutrients. GLP-1 receptor (GLP-1R) agonists applied peripherally or centrally decrease food intake and increase glucose-stimulated insulin secretion. These effects make the GLP-1 system an attractive target for the treatment of type 2 diabetes mellitus and obesity. In addition to these more frequently studied effects of GLP-1R stimulation, previous reports indicate that GLP-1R agonists suppress water intake. The present experiments were designed to provide greater temporal resolution and site specificity for the effect of GLP-1 and the long-acting GLP-1R agonists, exendin-4 and liraglutide, on unstimulated water intake when food was and was not available. All three GLP-1R ligands suppressed water intake after peripheral intraperitoneal administration, both in the presence of and the absence of food; however, the magnitude and time frame of water intake suppression varied by drug. GLP-1 had an immediate, but transient, hypodipsic effect when administered peripherally, whereas the water intake suppression by IP exendin-4 and liraglutide was much more persistent. Additionally, intracerebroventricular administration of GLP-1R agonists suppressed water intake when food was absent, but the suppression of intake showed modest differences depending on whether the drug was administered to the lateral or fourth ventricle. To the best of our knowledge, this is the first demonstration of GLP-1 receptor agonists affecting unstimulated, overnight intake in the absence of food, the first test for antidipsogenic effects of hindbrain application of GLP-1 receptor agonists, and the first test of a central effect (forebrain or hindbrain) of liraglutide on water intake. Overall, these results show that GLP-1R agonists have a hypodipsic effect that is independent of GLP-1R-mediated effects on food intake, and this occurs, in part, through central nervous system GLP-1R activation.     

Drinking,but not feeding,is opiate-sensitive in hamsters

The long-lasting opiate antagonist, naltrexone (NTX), was examined for its effects on various types of consummatory behavior in male golden hamsters and rats. Rat, but not hamster, 24 hr food and water intakes were significantly decreased by four daily NTX (10.0 mg/kg) injections. Hamsters displayed a minimal night to day feeding ratio compared to rats. hamsters increased food intake following insulin (50 U/kg) administration, but not after 24 hr food deprivation (FD) or 2-deoxy-D-glucose (2-DG; 800 mg/kg) injections. NTX (1.0 and 10 mg/kg) had no effect on feeding, but markedly attenuated hamster drinking induced by 48 hr water deprivation or hypertonic saline injection. Dexamethasone (DEX), a glucocorticoid which depletes pituitary β-endorphin and produces anorexia in rats, had no effect on daily hamster intake. Since the normal feeding profile of the hamster is similar to that of naloxone and DEX-treated rats, hamsters appear to lack an opiate-sensitive feeding system. In contrast, stimulated drinking behavior of hamsters operates through an opiate-sensitive mechanism. Thus, there are marked species differences concerning the involvement of endogenous opioids is consummatory behavior.     

Effects of water deprivation on corticosterone production in the male Brattleboro rat genetically deprived of vasopressin

Effects of 72 h water-deprivation on plasma corticosterone concentration have been investigated in male Brattleboro rats homozygous for hypothalamic diabetes insipidus (DI) and in male Long-Evans rats (LE), as controls. To determine the global effect of water deprivation, drinking water deprived rats were compared with hydrated animals. Because water deprived rats showed a depressed food intake, to elucidate the specific effect of dehydration alone, drinking water deprived rats were compared with similar food-restricted but water supplied animals. Increases in adrenal weights and in plasma corticosterone content, following 72 h water-deprivation, were greater in DI than in LE rats. In LE rats, they seemed to be the result of both dehydration and denutrition. Conversely in DI rats lacking vasopressin, dehydration alone increased neither adrenal weights nor plasma concentration of corticosterone; the whole plasma corticosterone content was reduced. So, in DI rats, the global response to drinking water deprivation was essentially due to food restriction, whose effect was partly suppressed by dehydration. Whatever the circumstances, plasma concentrations of corticosterone were higher in DI than in LE rats. Interrelationships between water deprivation, stress, vasopressin and glucocorticoids are discussed.     

Loss of morphine hyperphagia following neonatal monosodium glutamate treatment in rats

Morphine stimulates food intake in mildly-deprived and nondeprived rats. Neonatal administration of monosodium glutamate (MSG) destroys the medial-basal hypothalamus and other circumventricular organs, including cells containing beta-endorphin that project to other hypothalamic nuclei proposed in the modulation of morphine hyperphagia. Food intake of MSG-treated and control rats were assessed following vehicle and morphine (1.0-5.0 mg/kg, sc) treatment in a mild (5h) food deprivation paradigm. Morphine hyperphagia was found to be absent in MSG-treated rats, although they responded normally to mild deprivation following vehicle treatment. These results add to the types of ingestive deficits observed in the MSG-treated rat, and suggest that the circumventricular system in general, and opioid medial-basal hypothalamic cells in particular may be implicated in morphine hyperphagia.     

Diazepam-induced cleft palate in the mouse and lack of correlation with the H-2 locus

Cleft palate frequencies were studied in AJ and SW mice following either 1- or 2-day dosing schedules with the anxiolytic drug diazepam (DAZ). In all cases, mice were food and water deprived for 24 and 48 hours in the 1- and 2-day dosing schedules, respectively. High cleft palate frequencies in control mice of both strains resulting from 48-hour food and water deprivation (on days 13.5 and 14.5 of gestation) were reduced in mice deprived for 24 hours, indicating a stress related effect. Two-day dosing with DAZ (400 mg/kg) produced a net increase in cleft palate frequency in SW (33%) and AJ (18%) mice. Mice treated only on day 13.5 had reduced control and DAZ cleft palate frequencies, neither of which were significant. Clefting was significant but reduced following 1-day dosing on day 13/20 of gestation (13 days 20 hours) in SW mice (18%), whereas no clefting was seen in the AJ strain. This strain difference was shown not to be related to differences in developmental timing. Production of cleft palate seen in AJ mice after 2 days of dosing may be indicative of an interaction of DAZ with the stresses resulting from food and water deprivation. Genes of the major histocompatibility locus, H-2, have been shown to regulate cleft palate formation following glucocorticoid and phenytoin administration to mice. Despite pharmacological similarities between DAZ and phenytoin, comparison of cleft palate frequencies following administration of DAZ to various strains of mice of different H-2 haplotypes indicated that genes associated with the H-2 locus do not regulate DAZ-induced cleft palate in these strains.     

Naloxone suppresses intake of highly preferred saccharin solutions in food deprived and sated rats

In repeated tests naloxone (1 mg/kg, sc) suppressed intake of a narrow range of highly preferred saccharin concentrations (0.1 and 1.0%) in nondeprived male rats but a wider range of concentrations (.001-1.0%) following 10 hr. food deprivation. In sated rats a low dose of morphine (0.1 mg/kg, sc) had no effect on intake of low concentrations of saccharin but significantly facilitated intake of the highest (10%) and least preferred concentration. These data support the hypothesis that endogenous opioids can modulate the affective quality of gustatory stimuli.     

Suppression by naloxone of water intake induced by deprevation and hypertonic saline in intact and hypophysectomized rats

Naloxone, an opiate antagonist, was administered to intact and hypophysectomized male rats following hypertonic saline pretreatment or 12 hr water deprivation. Water intake following hypertonic saline or water deprevation was reduced by 0.01 – 10 mg/kg of naloxone in a dose-related fashion in both intact and hypophysectomized rats. Water consumption induced by hypertonic saline administration appeared to be more susceptible to the suppressant effects of naloxone than did that evoked by water deprevation. These results demonstrate that naloxone reduces water intake in the rat following intracellular dehydration by hypertonic saline administration, as well as after general dehydration induced by water deprevation. Furthermore, the suppressant effects of naloxone on water intake do not appear to involve pituitary endorphins, although a possible involvement of antidiuretic hormone in these effects cannot be excluded.     

Naloxone reduction of stress-related feeding

The effects of the narcotic antagonist, naloxone, on various types of stress- related feeding in rats were examined. Tail pinch-induced eating of a palatable substance, and 3 hr daytime rat chow intake following acute 2-deoxy-D-glucose (2-DG, 400 mg/kg) administration or 24 hr food deprivation were significantly decreased by low doses (1 mg/kg) of naloxone. Night time food intake was likewise decreased by naloxone (4 mg/kg). In contrast, hyperphagia induced by insulin (10 U/kg) was not decreased by naloxone (0.06–16 mg/kg). These findings suggest that narcotic antagonists should be considered as possible anorexics selective for stress-induced eating, and that endogenous opiates may prove to be another significant factor involved in the control of food intake.     

Dehydration anorexia is attenuated in oxytocin-deficient mice

Evidence in rats suggests that central oxytocin (OT) signaling pathways contribute to suppression of food intake during dehydration (i.e., dehydration anorexia). The present study examined water deprivation-induced dehydration anorexia in wild-type and OT -/- mice. Mice were deprived of food alone (fasted, euhydrated) or were deprived of both food and water (fasted, dehydrated) for 18 h overnight. Fasted wild-type mice consumed significantly less chow during a 60-min refeeding period when dehydrated compared with their intake when euhydrated. Conversely, fasting-induced food intake was slightly but not significantly suppressed by dehydration in OT -/- mice, evidence for attenuated dehydration anorexia. In a separate experiment, mice were deprived of water (but not food) overnight for 18 h; then they were anesthetized and perfused with fixative for immunocytochemical analysis of central Fos expression. Fos was elevated similarly in osmo- and volume-sensitive regions of the basal forebrain and hypothalamus in wild-type and OT -/- mice after water deprivation. OT-positive neurons expressed Fos in dehydrated wild-type mice, and vasopressin-positive neurons were activated to a similar extent in wild-type and OT -/- mice. Conversely, significantly fewer neurons within the hindbrain dorsal vagal complex were activated in OT -/- mice after water deprivation compared with activation in wild-type mice. These findings support the view that OT-containing projections from the hypothalamus to the hindbrain are necessary for the full expression of compensatory behavioral and physiological responses to dehydration.     

Neurotensin: effects of hypothalamic and intravenous injections on eating and drinking in rats

To investigate a role for the brain-gut peptide neurotensin (NT) in ingestive behavior, changes in food and water intake of food-deprived rats were examined following injection of NT into the paraventricular hypothalamic nucleus (PVN) or the mesenteric vein. Unilateral PVN NT (2.5, 5.0, 10.0 micrograms/0.3 microliter) produced substantial dose-dependent reductions in total food intake 0.5, 1, and 4 hr postinjection. In contrast, PVN NT had no effect on water intake and produced no change in grooming, rearing, sleeping, resting or locomotor activity. Bilateral PVN NT at a high dose (10.0 micrograms/side) suppressed consumption of solid or liquid diet in food-deprived rats, but did not affect water intake in water-deprived rats. This specificity is consistent with a role for CNS NT in feeding behavior. Intravenous NT (1-1000 pmole/kg/min for 30 min) did not specifically suppress food intake; however, low doses did increase water intake in food-deprived rats. These findings do not support a role for plasma NT in feeding, but do suggest that it may play a role in drinking behavior.