Oxytocin inhibits food and fluid intake in rats

Increasing evidence indirectly suggests a role for oxytocinergic neurons in the control of ingestive behaviors. The present study was aimed at directly investigating a possible effect of oxytocin on food and water intake in rats. Oxytocin, whether administered intracerebroventricularly (ICV) (1-10 micrograms/rat) or intraperitoneally (IP) (375-3,000 micrograms/kg) dose dependently inhibited food intake in freely feeding animals; in schedule-fed animals fasting for 21 h, oxytocin not only reduced food intake but also reduced the time spent eating and increased the latency to first meal. On the other hand, oxytocin antagonist d(CH2)5Tyr(Me)-[Orn8]-vasotocin, ICV injected at the dose of 10 micrograms/rat, increased food intake and time spent eating and reduced the latency to first meal; moreover, it completely prevented the effect of oxytocin. Water intake was studied both in freely drinking animals and in three different models of thirst (water deprivation, hypertonic saline administration, angiotensin II injection). In all cases, oxytocin dose dependently inhibited water intake, in a dose range of 0.1-10 micrograms/rat (ICV) or 93-750 micrograms/kg (IP). In the water deprivation model, ICV pretreatment with d(CH2)5Tyr(Me)-[Orn8]-vasotocin completely prevented the antidipsogenic effect of oxytocin. In conclusion, these data show that oxytocin directly inhibits food and water intake in rats, the effect being specifically mediated by brain oxytocin receptors. This may support the idea that the brain oxytocinergic system plays an important role in the regulation of ingestive behaviors.     

Operant feeding and drinking in pigs following intracerebroventricular injection of synthetic cholecystokinin octapeptide

Operant feeding and drinking was investigated in food- or water-deprived pigs following intracerebroventricular (ICV) injection of a saline solution containing synthetic cholecystokinin (CCK) octapeptide. In 17-hour food-deprived animals treated with 0, 5, 10, 20 or 40 units ICV, post-treatment food intake was significantly reduced in a dose-related manner but drinking was unaffected. In 22-hour water-deprived pigs treated with 0, 10 or 40 units CCK octapeptide ICV, no effect on drinking was apparent. Pigs injected intravenously with 40 units following 17 hours food deprivation did not reduce their food intake.     

Effects of intracerebroventricular injection of muscimol or GABA on operant feeding in pigs

Young pigs were prepared with lateral intracerebroventricular (ICV) cannulae. They were housed individually in cages fitted with operant panels and could obtain food and water ad lib. The GABA-A receptor agonist muscimol (25-200 nmol) ICV produced an increase in food intake in which the dose-response relation was most obvious 30-60 min after dosing. The 25-nmol dose had no effect on feeding. However, muscimol (50 nmol) caused a significant increase in feeding (p less than 0.01) during the first 30 min after injection, while the 100- and 200-nmol doses increased food intake (p less than 0.01) during the first 60 min. The effect of muscimol (100 nmol) on food intake was completely abolished by the simultaneous administration of the GABA-A receptor antagonist bicuculline (100 nmol). GABA (40-1600 nmol) ICV also produced a dose-related increase in food intake (p less than 0.01) in the 15 min after injection. Only doses of 800 nmol and above were effective. The effects of GABA (1600 nmol) were completely abolished by the simultaneous administration of bicuculline (50 nmol). Neither muscimol nor GABA influenced food intake for the 24-hr time period or water intake during any time period. The results indicate that stimulation of central GABA-A receptors induces operant feeding in the satiated pig.     

Central administration of corticotropin releasing factor in the pig: effects on operant feeding, drinking and plasma cortisol

Four experiments were carried out to investigate the effects of corticotropin releasing factor (CRF) on ingestive behaviour and cortisol secretion in the prepubertal pig. In Experiment 1, 19-hr food-deprived animals were given intracerebroventricular (ICV) injections of 2.5, 10 or 20 micrograms CRF, or saline vehicle, 5 min after the start of a 30-min operant-feeding session. The total number of food reinforcements obtained in the posttreatment period did not change after 2.5 or 10 micrograms CRF, although the latter dose reduced intake in the final 5 min of the test; overall food consumption, however, was reduced after 20 micrograms CRF. In Experiment 2, pigs were treated intravenously with 20 micrograms CRF, or saline, using the same test situation as in Experiment 1; neither treatment significantly affected operant feeding. In Experiment 3, 19-hr water-deprived pigs were given ICV injections of 20 micrograms CRF, or saline, 15 min before the start of a 30-min operant-drinking session. Water intake was increased in the 5-min period directly after CRF injection, but there was no overall reduction in drinking. In Experiment 4, blood samples were taken at 15-min intervals for 30 min before and 90 min after ICV injection of 20 micrograms CRF, or saline, in food and water replete animals. Both treatments appeared to increase plasma cortisol levels, as determined by radioimmunoassay, but the effect was more pronounced after CRF.     

Unique contribution of catecholamine receptors in the brain of the cat underlying feeding

After a Collison cannula was implanted bilaterally in the cat for intracerebroventricular (ICV) injection, individual patterns of food intake were determined. A mixture of dry and canned cat food was provided to the animal every morning at the same time for 1.0 hr. Once intakes had stabilized, either norepinephrine (NE) or an adrenoreceptor blocking agent was infused in one lateral ventricle by gravity flow over an interval of 30-60 sec. NE given ICV in a dose of 25-75 micrograms 15 min before the period of feeding enhanced both the amount of food consumed by the cat and the duration of its feeding for up to 1.0 hr. When phentolamine in a dose of 25-100 micrograms was infused 15 min prior to the feeding interval, the cat's intake of food was attenuated in a dose-dependent manner, again in terms of both the quantity consumed and the interval of eating. Propranolol was essentially without effect on food intake. In the fully satiated cat, NE infused ICV 15-45 min following the termination of its morning feeding episode tended to augment food intake at the highest 100 micrograms dose, but the effect was not significant. The dose-dependent hypothermia typically observed after NE is given ICV to the cat was found to be entirely independent of the feeding response. Overall, these findings show that noradrenergic pathways in the cat's feeding system apparently bias or otherwise modulate the amount of food consumed. As in other species, the feeding mechanism appears to be mediated through alpha-adrenergic receptors presumed to be in the diencephalon of the cat.     

Influence of regimen and insulinemia on orexigenic effects of GRF1-44 in sheep

The effects of intracerebroventricular (ICV) and intravenous (IV) administration of human GRF1-44 on feeding behavior were tested in hay- and concentrate-fed non lactating ewes. Administered ICV 5 min prior to hay disposal in 16 hr fasted ewes, GRF1-44 increased the first 3 hr and daily (8 hr) food intake by 25.3 and 24.5% respectively; this corresponded to a higher rate of ingestion during the first 3 hr. Similar effects on feeding behavior were observed after IV administration of a 10-times greater dose of GRF1-44 (1 microgram X kg-1), with daily hay consumption increasing from 1125 +/- 44 g (control) to 1407 +/- 91 g. In contrast, food intake of concentrates was significantly (p less than 0.05) higher only during the first hour of feeding and the daily food intake was unchanged. Both ICV (40 mU X kg-1) and IV (400 mU X kg-1) administrations of insulin did not affect feeding behavior per se, but suppressed the increased food intake of hay induced by IV GRF1-44. It is concluded that the orexigenic effects of GRF1-44 are probably centrally mediated and depend on regimen and digestive status. It is suggested that the insulin response to a meal of concentrates may be responsible for the early blockade of the orexigenic effects of GRF.     

Effects of calcitonin and CGRP alone or in combination on food intake and forestomach (reticulum) motility in sheep

The effects of intracerebroventricular (ICV) and intravenous (IV) administration of calcitonin and calcitonin gene-related peptide (CGRP) on feeding behavior and reticular motility were investigated in sheep. ICV calcitonin at a dose of 2 to 200 mU/kg reduced, in a dose-related manner, the immediate (0-60 min) food intake. The daily food intake was also significantly (p less than 0.05) decreased for doses up to 20 mU/kg, and the frequency of reticular contractions during the first hour of eating was decreased by 27.9%. Calcitonin at the highest IV dose (200 mU/kg) did not affect feeding behavior or reticular motility. In contrast, CGRP given ICV did not affect the first 3 hour period of food intake, while a significant increase (27.8%) in daily food intake was observed at a dose of 20 ng/kg despite immediate inhibitory effects on reticular frequency. No effect on feeding behavior and forestomach motility was noticed for a 25 times higher dose IV administered. Furthermore, CGRP given ICV (100 ng/kg) did not antagonize the immediate anorectic effects of calcitonin (200 mU/kg), although it delayed commencement of rumination and partially restored the daily food intake. These results suggest that calcitonin and CGRP play opposite roles in the central control of food intake in sheep, probably by acting on different brain structures, yet have a similar effect on reticular motility.     

Effects of the CCK receptor antagonist MK-329 on food intake in pigs

The cholecystokinin (CCK) receptor antagonist MK-329 (previously L364,718) was administered intravenously (IV) (17.5-140 micrograms/kg) to pigs trained to make operant responses for food reinforcements after 4 hr of food deprivation. MK-329 produced a dose-related increase in food intake during the 2-hr test period, with maximum increases occurring at a dose of 70 micrograms/kg. CCK (1 micrograms/kg IV) produced a short-term reduction in feeding and this effect was completely abolished by pretreating the animals with MK-329 (70 micrograms/kg). The present results lend support to the hypothesis that endogenous CCK is involved in satiety.     

Structure-function analysis of stimulation of food intake by neuropeptide Y: effects of receptor agonists.

Neuropeptide Y (NPY) is a potent natural orexigenic signal in the rat. In this study, we have compared the effects of several COOH-terminal fragments of NPY and NPY receptor agonists on cumulative food intake in male rats. Rats were implanted with permanent cannulae either into the third cerebroventricle or paraventricular nucleus (PVN). NPY1-36 and various COOH-terminal fragments of NPY, two agonist analogues [Leu31, Pro34]NPY and NPY 1-4-Aca (epsilon-amino-caproic acid)-25-36, were administered intracerebroventricularly (ICV) or directly into the PVN, and the cumulative 2-h food intake response was compared. We observed that peptides that were effective by ICV were also effective when administered into the PVN, but smaller amounts of the peptides were required after PVN injection to evoke an equivalent food intake response. Injection of NPY1-36 induced a dose-dependent increment in food intake. Surprisingly, deletion of NH2-terminal tyrosine residue did not adversely affect feeding behavior. In fact, NPY2-36 was consistently more effective than NPY1-36; the enhancement in feeding by NPY2-36 was dose-related and was higher than evoked by NPY1-36 at each dose tested. Further serial deletion of aminoacids at NH2-terminal resulted in complete loss of activity. In addition, NPY agonist analogue, NPY 1-4-Aca-25-36, failed to stimulate feeding. However, NPY Y1 receptor agonist, [Leu31, Pro34]NPY, but not Y2 receptor agonist, NPY13-36, stimulated feeding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Some determinants of intake and patterns of feeding in the guinea pig

Regulation of food and water intake was studied in young and adult Guinea pigs by continuously monitoring ad lib feeding and drinking patterns and by examining the response to levels of celluflour dilution that ranged from 20–75%. Meal size and the duration of the intermeal interval were not systematically related to the sizes of preceding meals or interval lengths. Variations in food intake were mediated almost entirely by changes in meal size. This parameter increased during growth, was elevated in the first meal following food deprivation, decreased when water was withheld and increased when water was returned. The probability of drinking within 20 min of eating was 0.80. Celluflour dilution led to a decrease in apparent caloric intake without a proportional decrease in body weight. Regulation of energy balance and meal to meal control of feeding in this monogastric, herbivorous rodent is discussed in relation to the Guinea pig's digestive physiology and ecological niche.     

Histamine in brain may have no role for histaminergic control of food-related drinking in the rat

Adult male Sprague-Dawley rats surgically fitted with a cannula positioned in the third cerebral ventricle were tested for drinking after exogenous histamine or after eating with or without antagonism of H1 and/or H2 receptors for histamine using intracerebroventricular (ICV) dexbrompheniramine (DXB; 12.5-50 micrograms) or cimetidine (C; 25-100 micrograms). Histamine (0.06-16 micrograms) given ICV failed to elicit drinking. For rats drinking in response to subcutaneous (SC) histamine, ICV DXB alone did not affect drinking, whereas ICV DXB plus C, and ICV C given alone inhibited drinking. Such inhibition appeared to be relatively selective for drinking elicited by SC histamine, because ICV 50 micrograms DXB plus 100 micrograms C abolished drinking elicited by SC histamine, but failed to inhibit drinking after 12-hr water deprivation. When rats ate and drank after food deprivation, ICV DXB alone and ICV DXB plus C did not significantly inhibit food-related water intake. The inhibition of food-related drinking by ICV 100 micrograms C given alone was accompanied by inhibition of eating. In summary, histamine had unimpressive dipsogenic effects when given ICV, ICV DXB and C inhibited drinking elicited by SC histamine, but ICV DXB and C failed to inhibit food-related drinking in a manner parallel to the selective effects of intraperitoneal injection of these drugs on drinking elicited by eating. This suggests that it is histamine and histamine receptors in the periphery rather than in brain that have the predominant role for a histaminergic mechanism for drinking elicited by eating in the rat, but our findings do not rule out a role(s) for histamine in brain in the control of ingestive behavior.     

Relationship between the concentration of cholecystokinin-like immunoreactivity in plasma and food intake in male rats

In food-deprived male rats IP injection of cholecystokinin octapeptide (CCK-8, 5 micrograms), ingestion of food or ejaculation caused a comparable increase in plasma concentrations of CCK-8 and inhibited food intake. IV injection of 0.1 microgram CCK-8 interrupted ongoing feeding and greatly increased plasma CCK-8 levels. Osmotic minipumps delivering 0.5 micrograms CCK-8/h implanted IP reduced meal size and caused a modest increase in plasma CCK-8 levels. Injection of 5 micrograms CCK-8 IP produced an abrupt but transient increase in plasma CCK-8 concentrations whereas plasma concentrations of CCK-8 increased gradually with feeding. Injection of 5 micrograms CCK-8 IP, but not feeding, caused a marked increase in plasma oxytocin levels. The suppression of feeding, but not the increase in oxytocin, induced by IP CCK-8 was reversed by ICV injection of the CCK antagonist proglumide in a dose (100 micrograms) which failed to affect food intake if injected IP. Deprivation of food decreased and feeding increased the concentration of CCK-like immunoreactivity in the CSF. It is suggested that CCK-8 inhibits feeding in physiological doses by a specific mechanism in which peripheral as well as central neural CCK is involved.     

Anorexia induced by toxohormone-L isolated from ascites fluid of patients with hepatoma.

To ascertain anorexigenic effect of toxohormone-L, a polypeptide extracted and purified from ascites of patients with hepatoma were infused into the rat third cerebroventricle. Food intake decreased on the first day after infusion of an optimum dose of 10.0 micrograms (p less than 0.05). The suppressive effect on feeding was linearly dose dependent (p less than 0.05). Meal size and latency to the first meal decreased in the 12-h dark period, and the first and the second 4-h cumulative blocks after infusion of a 10.0 micrograms dose (p less than 0.01 for each). The suppressive effects on total food intake and meal size were completely recovered within 24 h after infusion. Neither postprandial intermeal interval nor eating speed was affected. Periprandial drinking, a ratio of water intake to food intake, was not affected after infusion of 5.0 and 10.0 micrograms toxohormone-L. Infusion of a 10.0 micrograms dose showed no effect on ambulation. These findings suggest that anorexia and cachexia produced in cancer patients may essentially be due to the suppressive effect of toxohormone-L on food intake.     

Effects of the 5-HT1A receptor agonist 8-OH-DPAT on operant food intake in food-deprived pigs.

The effects of the 5-HT1A agonist 8-hydroxy-2 (di-n-propylamino)tetralin (8-OH-DPAT) were investigated on operant food intake in food-deprived pigs. In Experiment 1, 8-OH-DPAT (5-20 microg/kg) administered intravenously (i.v.) 15 min prior to the occurrence of feeding produced a dose-related decrease in operant food intake in pigs that had been fasted overnight. The effects were mainly apparent during the first 30 min after the start of the feeding period. In Experiment 2, 8-OH-DPAT (25 and 50 microg/kg, i.v.) administered 60 min prior to the occurrence of feeding in pigs that were fasted overnight also produced significant decreases in food intake. The effects were mainly apparent during the first 30-40 min after the start of the feeding period. In Experiment 3, 8-OH-DPAT (20 microg/kg, i.v.) significantly increased operant feeding in satiated pigs during the first 30 min after administration. These results show that 8-OH-DPAT has complex effects on feeding behaviour in pigs, increasing operant food intake in satiated pigs, while producing a reduction in food intake in food-deprived animals.     

Humoral and cardiovascular responses to feeding in pigs

In young pigs, allowed to feed after various periods of food deprivation, the changes in plasma levels of insulin, glucose, and corticosteroids were measured. Food was presented in bowls or obtained by operant response. In pigs deprived of food for 17 h there was a marked rise in insulin from 15 +/- 1 to 91 +/- 10 microU/ml and glucose from 94 +/- 2 to 112 +/- 4 mg/dl when feeding began, while the corticosteroid levels were reduced from 48 +/- 8 to 29 +/- 9 ng/ml. Evidence for a cephalic phase of insulin secretion was seen in 17-h fasted pigs. In pigs fed ad libitum there were no significant changes in the levels of insulin, glucose, or corticosteroids. The changes observed in the 5-h fasted pigs were intermediate. No differences were seen between bowl-fed and operant pigs. Pressure transducers were surgically implanted in the carotid arteries of three pigs. When 17-h fasted pigs started to eat there was a marked rise of blood pressure from 114 +/- 3 to 147 +/- 5 mmHg and a similar increase was seen when satiated pigs drank milk.     

Food deprivation dissociates pancreatic glucagon's effects on satiety and hepatic glucose production at dark onset

We compared the effects of different durations of pretest food deprivation on pancreatic glucagon's (PG) satiating and glycogenolytic actions in order to test the hypothesis that stimulation of hepatic glucose production causes PG's satiety effect. Rats were maintained on a 12:12 LD cycle (lights off: 1015) and deprived of food 45 min or 8, 12, 18, or 24 hr before intraperitoneal injection of 400 micrograms/kg PG. Testing began at 1015, the beginning of the dark phase. Food intake was not inhibited after 45 min of pretest food deprivation (30 min change, 2.5 +/- 4.0%, p greater than 0.05), but was inhibited after 8 or more hr food deprivation. The largest inhibitory effect, 16.2 +/- 3.8%, p less than 0.01, occurred after 8 hr food deprivation. In separate experiments, rats were food deprived 45 min or 8 hr, similarly injected, and killed 10 min after refeeding for blood and liver samples. Hepatic glycogen content at meal onset was higher in rats deprived 45 min than in rats deprived 8 hr (3.2 +/- 0.3 vs. 1.7 +/- 0.3% liver weight, p less than 0.01), and PG injection produced a higher level of hepatic vein blood glucose in the less deprived rats (196 +/- 5 vs. 168 +/- 12 mg/dl, p less than 0.05). Thus, in rats tested at the beginning of the dark phase of the LD cycle after 45 min or 8 hr food deprivation, there is an inverse relation between PG's potencies to inhibit food intake and to stimulate hepatic glucose production.(ABSTRACT TRUNCATED AT 250 WORDS)     

The differential effects of intravenously administered 8-OH-DPAT on operant food intake in satiated and food-deprived pigs are mediated by central 5-HT(1A) receptors

It has previously been shown that the intravenous administration of the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), increases food intake in satiated pigs and decreases food intake in fasted pigs. The present experiments were conducted to investigate the effects of central administration of the 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-N-2-pyridinyl-cyclohexane carbox-amide maleate (WAY 100635), on the stimulant and depressant effects of 8-OH-DPAT on operant food intake in satiated and hungry pigs. In Experiment 1, 8-OH-DPAT (25 microg/kg) produced an increase in operant feeding during the first 30 min following intravenous administration to satiated pigs. The 8-OH-DPAT-induced hyperphagia was completely abolished by pretreatment with WAY 100635 (0.3 mg) administered by intracerebroventricular injection. In Experiment 2, 8-OH-DPAT (25 microg/kg) administered intravenously 15 min prior to the onset of feeding in pigs that had been fasted for 22.5 h produced a decrease in operant food intake, which was most apparent during the first 30 min of the feeding period. The hypophagic effect was completely abolished by pretreatment with WAY 100635 (0.3 mg icv) administered 30 min before the start of the feeding period. In both experiments, WAY 100635 (0.3 mg icv) did not have any significant effects on feeding. The results of the present study extend previous results in the pig and show that both the hyperphagic and the hypophagic effects of 8-OH-DPAT in satiated and fasted pigs, respectively, are mediated by central 5-HT(1A) receptors.     

Effect of food deprivation and maintenance diet composition on fat preference and acceptance in rats

High-fat diets typically elicit greater kcal intake and/or weight gain than low-fat diets. Palatability, caloric density, and the unique postingestive effects of fat have each been shown to contribute to high-fat diet hyperphagia. Because long-term intake reflects the sum of many individual eating episodes (meals), it is important to investigate factors that may modulate fat intake at a meal. The present studies used high-fat (hi-fat) and high-carbohydrate (hi-carb) liquid diets (both 2.3 kcal/mL) to assess the effect of hunger level (0 versus 24-h food deprivation) and fat content of the maintenance diet (12 versus 48%) on fat preference (when a choice among foods is offered in a two-bottle test), and acceptance (only one food offered) in male rats. Preference for hi-fat relative to hi-carb (two-bottle test) was enhanced by 24-h food deprivation, and by a high-fat maintenance diet. In contrast, neither deprivation nor maintenance diet composition influenced relative meal size (one-bottle test) of hi-fat and hi-carb: irrespective of test conditions, meal size of hi-fat was bigger than meal size of hi-carb.     

Epinephrine inhibits feeding nonspecifically in the rat

The hypothesis that epinephrine (EPI) and pancreatic glucagon (PG) inhibit feeding by activating a common physiological satiety mechanism was tested by comparing the two agents' behavioral effects. In several tests of specificity, EPI and PG had functionally different inhibitory actions. Intraperitoneal injection of 6.25-50 micrograms/kg EPI and 100-400 micrograms/kg PG elicited overlapping dose-related inhibitions of intake of milk diet in rats maintained ad lib on pelleted chow. Twenty-five to 50 micrograms/kg EPI also elicited anomalous behaviors that are not normally associated with feeding, including supine postures with limbs extended and crawling with trunk dorsoflexed and abdomen pressed against cage floor. EPI elicited similar anomalous behaviors in rats that either sham fed with open gastric cannulas, drank after water deprivation, or were presented neither food nor water. Fifty to 200 micrograms/kg EPI also inhibited water intake in the thirsty rats, and 25-50 micrograms/kg EPI inhibited sham feeding. PG, in contrast, neither elicited anomalous behaviors nor inhibited water intake nor inhibited sham feeding. These data demonstrate that the inhibitory actions of exogenous EPI and PG are functionally dissociable. We conclude that 25-200 micrograms/kg EPI acts nonspecifically to produce anorexia and adipsia, while PG elicits postprandial satiety.     

Time course and response specificity of prolactin-induced hyperphagia in ring doves

Intracranial injections of prolactin (PRL) have been previously shown to elevate food and water intake in ring doves. In an attempt to further characterize these PRL-induced behavioral responses and the time course of PRL action, food and/or water intake were measured as frequent intervals in male doves given a single intracerebroventricular (ICV) injection of ovine PRL (44 pmoles) or vehicle under food deprivation, water deprivation, or nondeprivation conditions. PRL increased food consumption by 35-50% over baseline levels in water deprived and nondeprived doves, although response latencies (10 hr) and durations (greater than 24 hr) were considerably longer than those reported for other orexigenic peptides. Behavioral observations of nondeprived doves further revealed that PRL significantly increased total time spent feeding and average feeding bout duration. In contrast to this pattern, water intake remained unchanged in food deprived doves and was only marginally increased in nondeprived doves following PRL treatment. Collectively, these results suggest that PRL promotes a selective and long-lasting hyperphagia which may in turn augment drinking activity.