Calcitonin effect on the dipsogenic response to intra-cerebroventricular administration of angiotensin II

Evidence indicates that intra-third cerebroventricular (III-ICV) administration of calcitonin suppresses food and water intake of rats. The purpose of this study was to determine whether calcitonin would influence angiotensin II-induced dipsogenesis when simultaneously administered III-ICV. Administration of calcitonin (0.5 U/rat) suppressed food and water intake in male Wistar rats. III-ICV administration of angiotensin II (100 ng/rat) to rats provided with ad lib food and water elicited short latency drinking without affecting food intake. III-ICV administration of calcitonin (0.5 U/rat) did not affect the drinking-inducing response to 100 ng/rat of angiotensin II when administered simultaneously. The results suggest that decrease in water intake by III-ICV calcitonin may be a consequence of the food intake suppression, i.e., reduced prandial drinking.     

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.     

Intracerebroventricular administration of a specific IL-1 receptor antagonist blocks food and water intake suppression induced by interleukin-1 beta.

Intracerebroventricular (ICV) microinfusion of recombinant human interleukin-1 beta (rhIL-1 beta, 1.0 ng/rat) suppressed the short-term (2 h) food and water intakes in rats. ICV infusion of recombinant human IL-1 receptor antagonist (rhIL-1ra) had no effect on food or water intake. Concomitant ICV infusion of rhIL-1 beta (1.0 ng/rat) and increasing concentrations of rhIL-1ra (25 to 1000 ng/rat) resulted in a dose-dependent inhibition of the short-term food and water intake suppression induced by rhIL-1 beta. The highest doses of rhIL-1ra (500 and 1000 ng/rat) completely blocked the food and water intake suppression induced by rhIL-1 beta. This suggests specificity of IL-1 beta suppression of short-term feeding and drinking by a direct action in the central nervous system (CNS). This ability of rhIL-1ra may have potential therapeutic implications in acute and chronic pathological processes associated with increased levels of IL-1 and appetite suppression.     

Ingestion, body weight and activity of rats receiving repeated intracerebroventricular infusions of rat satietin

Satietin is a putative satiety agent that is found in a variety of species including man and the rat. In the first experiment male Sprague-Dawley rats were fitted with chronic third ventricle cannulas and placed in activity wheels. After recovery, animals were intracerebroventricularly (ICV) infused with either sterile rat satietin (r-SAT) (100 micrograms/rat) dissolved in 10 microliters saline (n = 6) or sterile saline (n = 8). Infusions were repeated the next two days. Infusions of r-SAT had no effect on the rats' water intake or activity but did suppress (p less than 0.05) their food consumption when compared to the controls, but only after the first and second infusions. Thus tolerance to r-SAT quickly developed using this schedule of administration. Notably, body weight of the r-SAT infused rats remained attenuated (p less than 0.01) for four days following the first infusion. In the second experiment the rats were ICV infused every fourth day with either r-SAT (100 micrograms/rat) (n = 10) or saline (n = 8) for a total of three infusions. Food, but not water, intake was significantly suppressed after the first and second infusions and lowered nonsignificantly after the third. Body weight was significantly reduced after the first r-SAT infusion and remained statistically reduced for seven days after the third infusion; at a time when the rats' food intake was normal. These data suggest that in addition to a r-SAT suppression of feeding, other r-SAT induced changes (possibly metabolic) may help reduce the rats' body weight. The above dose of r-SAT had no affect on the animals' rectal temperature. The data of the above two experiments reveal that r-SAT infused ICV into rats can suppress the animals' food intake and lead to a prolonged attenuation of body weight.     

Food intake and serum insulin responses to intraventricular infusions of insulin and IGF-I.

Previous studies reported that intracerebroventricular (ICV) infusion of insulin decreased food intake in rats and baboons. Insulin can bind to insulin-like growth factor I (IGF-I) receptors and mimic the response of IGF-I. Our objective was to determine the effects of ICV infused-insulin or IGF-I on food intake in sheep. In the present study, a 6-day ICV infusion of insulin (123 ng/kg of body weight/day) but not of IGF-I (123 ng/kg of body weight/day) decreased food intake by 40% (p less than 0.003) and body weight (p less than 0.015) compared with control sheep. In addition, sheep that received ICV insulin or IGF-I had only half the concentration of insulin in serum as compared with controls. Our results support the hypothesis that ICV insulin does not decrease food intake through IGF-I receptors. Nevertheless, apparently both insulin and IGF-I in the brain can influence the concentration of insulin in blood.     

Evidence for a physiological role of central calcitonin gene-related peptide (CGRP) receptors in the control of food intake in rats

In the present study, we investigated the role of central calcitonin gene-related peptide (CGRP) and amylin receptors in mediating the anorectic effects of CGRP and amylin in rats chronically cannulated in the lateral brain ventricle. Intracerebroventricular (ICV) injection of the CGRP and amylin receptor antagonist CGRP(8–37) failed to influence the anorectic effects of peripherally injected CGRP and amylin. CGRP(8–37) alone, however, increased food intake in food deprived rats when administered 2 h before food presentation. Under the same experimental conditions, the more specific amylin receptor antagonists amylin(8–37) or AC 187 did not affect food intake. We therefore conclude, that CGRP is a physiological regulator of food intake within the central nervous system, acting at central CGRP receptors. Peripheral receptors, however, are likely to mediate the anorectic effects of peripherally administered amylin and CGRP.     

The effect of continuous intracerebroventricular infusion of satietin on ingestion, activity and body weight of rats

Satietin is a putative satiety agent when given either peripherally or intracerebroventricularly (ICV). In the present study male Sprague Dawley rats were fitted with chronic third ventricle cannulas. After recovery, Alzet seven day osmotic pumps were inserted subcutaneously and tubing was connected to the cannula. Rats were then infused ICV with saline or semi-purified human satietin (25 micrograms/day; 1 microliter/hr). In the satietin group, daily chow intake was reduced (p less than 0.05) on days 1 and 2, recovered to control levels on days 4 and 5 and again declined (p less than 0.05) on days 6-8. During this latter period the satietin treated animals appeared ill. The satietin group's water intake paralleled food consumption, whereas the groups' water/food intake ratios did not differ. Satietin infusions decreased (p less than 0.01) the rats' body weight 42 grams by day 4, whereas the control group's weight remained constant. Even during the period where the satietin group's food intake returned to control levels they continued to lose weight. Running wheel activity was reduced throughout the satietin infusion period even when food and water ingestion had returned to control levels. The data suggest that semi-purified human satietin, when tested in rats, is an anorexogenic agent, however, its continuous use quickly produces tolerance and later what may be a cross-species allergic reaction (due to the satietin itself or a contaminant). The appropriateness of testing semi-purified satietin in the rat model is questioned.     

Intracerebroventricular infusions of rat satietin into rats does not produce conditioned taste aversion

In a previous study we found that while human satietin (h-SAT) suppressed the food intake of rats it was also aversive to them. In the present study rat satietin (r-SAT) was tested for aversiveness in rats fitted with chronic third ventricle (ICV) cannulas. The rats were then given access to water for 1-hr/day and food ad lib for ten days. Fluid intake, food intake during fluid access and 24-hr total food consumption were recorded. The rats were then ICV infused with saline and 30 min later half of the animals given access to banana flavored water (Group 1) while the remainder were presented with almond flavored water (Group 2). The next day Group 1 was infused with saline and Group 2 with 100 micrograms/rat of r-SAT. Thirty minutes later the flavors presented to the rats were the reverse of the previous day. Satietin significantly reduced food intake during fluid access and for 24 hours. Thereafter, fluid and food ingestion of the groups was normal and similar. Thus no rebound feeding occurred in the r-SAT treated group. Two days after r-SAT or saline the rats were given a two-bottle choice test. Both groups displaced equal preference for the flavors, therefore r-SAT produced no taste aversion. The r-SAT treated rats lost more body weight than saline treated animals the first day after treatment. This difference increased the next day and remained significant for seven days post infusion, whereas, food consumption did not differ between the groups after the first day. The data indicate the food intake suppression in rats produced by r-SAT is not due to the compound being aversive.     

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.     

The effect of ghrelin on water intake during dipsogenic conditions

Ghrelin has been studied extensively in the context of food intake and energy homeostasis, but less is known about its role in other ingestive behaviors. The present studies investigated the effects of this orexigenic peptide on both food and water intake during dipsogenic conditions. Specifically, animals were exposed to one of five dipsetic stimuli: (1) 24-h water deprivation, (2) replacement of drinking water with 2.5% NaCl, (3) peripheral administration of hypertonic saline, (4) ICV injection of angiotensin II (AngII), or (5) the combination of peripheral hypertonic saline and central AngII. Animals then were given an ICV injection of ghrelin (0.5  µg) or vehicle, and subsequent food and water intakes were measured. Ghrelin reliably increased food intake under each stimulus condition. Ghrelin also affected water intake, but with less consistency across the conditions. Specifically, ghrelin attenuated water intake stimulated by acute injection of AngII or hypertonic saline, but failed to affect drinking in the other three stimulus conditions. Investigation of the temporal pattern of food and water intakes in three of these dipsogenic conditions failed to support a role of different intake patterns in the observed differences in water intake by ghrelin-treated rats. Although the effect of ghrelin on water intake was not present in every dipsogenic condition, these data provide evidence that the actions of ghrelin are not limited to food intake, but can also include alterations in water intake.     

Food intake suppression in rats by a substance isolated from human feces

A substance which suppresses food intake was isolated from human feces. This substance was extracted and partially purified using Sephacryl S-200 column chromatography and a DEAE-Sephadex A-25 column chromatography. To assess the biological activity, rats were subjected to various applications. The intraperitoneal administration and the intracerebroventricular microinfusion of this substance suppresses short- and long-term food intake. The central infusion suppresses feeding with a potency over 1000 times that the peripheral administration. The central infusion of the heat-treated substance was without effect. These results suggest that a substance present in human feces (probably of a proteic nature) suppresses food intake in rats, at the level of the central nervous system.     

Chronic infusion of the amylin antagonist AC 187 increases feeding in Zucker fa/fa rats but not in lean controls

Numerous studies have established the pancreatic B-cell hormone amylin as an important anorectic peptide affecting meal-ending satiety. In the present study, we investigated the effect of a chronic infusion of the amylin antagonist AC 187 on food intake. The studies were performed using obese Zucker fa/fa rats, which are hyperamylinemic but have a defective leptin and insulin signaling system. A chronic intraperitoneal infusion of the amylin antagonist AC 187 (10 microg/kg/h) significantly increased dark phase and total food intake in Zucker but not in lean control rats. During the 8-day infusion experiment, AC 187 had no clear effect on body weight gain in either group. After acute administration, amylin and its agonist salmon calcitonin (sCT) equally reduced food intake in Zucker and lean control rats while cholecystokinin's (CCK) anorectic effect was weaker in the Zucker rats. We provide evidence for amylin being a potential long-term regulator of food intake because AC 187 increased food intake in obese fa/fa rats but not in lean control animals, which have low baseline amylin levels. Amylin may play some role as lipostatic feedback signal similar to leptin and insulin at least when the leptin and insulin feedback signaling systems are deficient. Despite basal hyperamylinemia in the Zucker rats, they do not seem to be less sensitive to the anorectic effects of amylin or its agonist sCT than respective controls. This contrasts with CCK whose anorectic action is reduced in Zucker rats when compared with lean controls.     

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.     

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.     

Evidence for cerebral sodium sensors involved in water drinking in sheep

Evidence supporting cerebral Na sensors in the initiation of thirst is the greater water drinking which occurs with intracerebroventricular (ICV) infusion of hypertonic NaCl than with ICV hypertonic saccharide solution. However, ICV infusion of hypertonic saccharide solution causes a reduction in CSF [Na], even though the saccharide is made in solution with normal [Na] of 150 mM. To prevent this, ICV infusion of hypertonic sucrose in high Na solution was made. The ICV infusion of 0.3 M sucrose/0.3 M NaCl-CSF caused water intake of 416 ± 173 ml (mean ± SEM) in 6 sheep, and CSF [Na] was 151 ± 0.9 mM, but ICV infusion of equiosmolar 0.45 M NaCl-CSF caused greater water intake of 1097 ± 202 ml and CSF [Na] increased to 178.8 ± 3.6 mM. Control ICV isotonic CSF did not cause drinking and CSF [Na] was 150.5 ± 0.8 mM whereas ICV 0.6 M sucrose-CSF ([Na]=150 mM) caused water intake of 132 ± 63 ml with CSF [Na] falling to 139.3 ± 1.3 mM. These results indicate specific brain NaCl sensors involved in thirst. Osmoreceptors may also exist because some drinking occurred with ICV sucrose despite reduced CSF [Na].     

Decreased feeding in rats following hepatic-portal infusion of glucagon

Male rats received a single hepatic-portal injection of glucagon following mild food deprivation. Cumulative food intake measured after 0.5–20 hr was decreased by the hormone. The absence of a concomitant decrease in water intake suggested a specific effect of glucagon on feeding. This specificity was further demonstrated by the use of an hepatic-portal infusion of glucagon as the unconditioned stimulus for the formation of a conditioned taste aversion which failed to produce avoidance of a novel taste. In contrast, pairing the taste with an intraperitoneal injection of lithium chloride did produce a learned taste aversion. Thus, the decreased feeding following infusion of a low concentration of pancreatic glucagon through a chronic hepatic-portal cannula cannot be attributed to visceral malaise. The relatively specific effect of this hormone on short-term feeding probably results from the activation of hepatic glycogenolysis, with the long-term effect on feeding possibly due to gluconeogenesis.     

The role of GABAergic system on the inhibitory effect of ghrelin on food intake in neonatal chicks

Ghrelin is a gut-brain peptide that has a stimulatory effect on food intake in mammals. In contrast, this peptide decreases food intake in neonatal chicks when injected intracerebroventricularly (ICV). In mammals, neuropeptide Y (NPY) mediates the orexigenic effect of ghrelin whereas in chicks it appears that corticotrophin releasing factor (CRF) is partially involved in the inhibitory effect of ghrelin on food intake. Gamma aminobutyric acid (GABA) has a stimulatory effect on food intake in mammals and birds. In this study we investigated whether the anorectic effect of ghrelin is mediated by the GABAergic system. In Experiment 1, 3 h-fasted chicks were given an ICV injection of chicken ghrelin and picrotoxin, a GABA_A receptors antagonist. Picrotoxin decreased food intake compared to the control chicks indicating a stimulatory effect of GABA_A receptors on food intake. However, picrotoxin did not alter the inhibitory effect of ghrelin on food intake. In Experiment 2, THIP hydrochloride, a GABA_A receptor agonist, was used in place of picrotoxin. THIP hydrochloride appeared to partially attenuate the decrease in food intake induced by ghrelin at 30 min postinjection. In Experiment 3, the effect of ICV injection of chicken ghrelin on gene expression of glutamate decarboxylase (GAD)₁ and GAD₂, GABA synthesis enzymes in the brain stem including hypothalamus, was investigated. The ICV injection of chicken ghrelin significantly reduced GAD₂ gene expression. These findings suggest that ghrelin may decrease food intake in neonatal chicks by reducing GABA synthesis and thereby GABA release within brain feeding centers.     

The satiety effects of intragastric macronutrient infusions in fatty and lean Zucker rats

To evaluate satiety in the hyperphagic, genetically obese Zucker “fatty” (fafa) rat, food-deprived fatty and lean (FaFa) control rats were given equicaloric intragastric infusions consisting largely of fat, carbohydrate, or protein. Relative to distilled water infusion, these infusions resulted in immediate reductions of food intake in both fatty and lean rats allowed to feed 20 min post-infusion. Cumulative food intakes remained reduced throughout the 2 hr period of observation. Thus, despite its hyperphagia, the fatty rat is responsive to the satiating effect of infused nutrients. However, the relative satiating effectiveness of the macronutrient infusions differed for the two genotypes. In lean rats, the different macronutrient infusions resulted in equivalent reductions of feeding. In contrast, in fatty rats, fat was the least satiating and protein was the most satiating macronutrient. Moreover, compared to lean rats, fatty rats displayed less initial suppression of feeding after fat infusion and greater overall suppression after protein infusion. These effects are consistent with the long-term feeding behavior of the fatty rat for the different macronutrients and may be related to pre- and postabsorptive metabolic alterations that have been documented in this animal.     

The effect of intravenous infusion of antidiuretic hormone on water intake in the rat

1. In rats the continuous I.V. infusion of ADH at rates up to 6.0 mu. kg(-1) min(-1) decreased drinking caused by water deprivation, by a 10% increase in osmotic pressure, and by caval ligation.2. Infusion of ADH at rates between 0.07 and 6.0 mu. kg(-1) min(-1) never potentiated drinking nor did it significantly affect the 24 hr water intake of rats that were in water balance at the start of the experiment.3. Urine output was slowed by a rate of infusion (13.0 muu. kg(-1) min(-1)) which was approximately 150 times smaller than the lowest rate which was found to decrease water intake.4. Since the rates of infusion of ADH which directly affect water intake and urine flow are so different, it is unlikely that ADH is a general homoeostatic hormone which controls both thirst and urine output in the rat.     

Pathophysiological significance of brain acidic fibroblast growth factor.

The acidic fibroblast growth factor (aFGF) in rat cerebrospinal fluid (CSF) increased 1000 times in the 2 hr period after food intake, or intraperitoneal (IP) or intracerebroventricular (ICV) glucose infusion. It diffused into the brain parenchyma and was taken up into neurons in the hypothalamus, hippocampus, etc.... aFGF is produced in the ependymal cells and released into CSF in response to increased glucose. ICV application of aFGF dose dependently inhibits, and anti-aFGF antibody facilitates food intake. IP injection of glucose 2 hr before a task that combined acquisition with passive avoidance significantly increased retention of avoidance by mice tested 24 hr later. In a Morris water maze task, IP glucose injection 2 hr before a first trial block reduced time to find and climb onto a platform hidden just below the water surface. These facilitation by glucose of affective and spatial memory were abolished by pretreatment with anti-aFGF antibody applied ICV. Continuous ICV infusion of aFGF into rats also significantly increased the reliability of passive avoidance for several days. The memory facilitation by aFGF was significantly attenuated by CA1 neuron death in the hippocampus caused by 5 min ischemia of the brain, in gerbils. After food intake, centrally-released aFGF reaches the hippocampus and facilitates memory, while peripherally released cholecystokinin reaches the endings of the afferent vagal nerves in the portal vein and changes the vagal nerve activity, which modulates hippocampal activity, to lead to memory facilitation. This, however, is blocked by vagotomy below the diaphragm.(ABSTRACT TRUNCATED AT 250 WORDS)