Effects of selective cholecystokinin antagonists L364,718 and L365,260 on food intake in rats

The selective type A and B cholecystokinin (CCK) receptor antagonists L364,718 and L365,260 were used to identify the receptor subtype that mediates the satiety effect of endogenous CCK. Male rats (n = 12–13/group), fed ground rat chow ad lib, received L364,718 (0, 1, 10, 100, or 1000 μg/kg IP) or L365,260 (0, 0.1, 1, 10, 100, 1000, or 10,000 μg/kg IP) 2 h after lights off, and food intake was measured 1.5, 3.5, and 5.5 h later. L364,718 significantly stimulated 1.5-h food intake by more than 40% at 10 μg/kg and higher doses; cumulative intake at 3.5 and 5.5 h remained elevated by about 20% at 1000 and 100 μg/kg of L364,718, respectively. In contrast, L365,260 had no significant stimulatory effect on feeding at any dose. The potency of L365,260 for antagonizing gastrin-stimulated gastric acid secretion was examined in unanesthetized rats. Male rats (n = 14), prepared with gastric and jugular vein cannulas, received doubling doses of gastrin (G-17I) (0.16–5 nmol/kg/h IV), each dose for 30 min, and gastric juice was collected for each 30-min period. G-17I stimulated gastric acid output dose dependently; the minimal effective dose was 0.16 nmol/kg/h, while maximal output (5-fold above basal) occurred at 5 nmol/kg/h. L365,260 (0, 1, 10, 100, 1000, or 10,000 μg/kg IV), administered 30 min before continuous infusion of G-17I (1.25 or 5 nmol/kg/h), significantly inhibited acid output only at 10,000 μg/kg; cumulative 60-min output was decreased by 60%. These results suggest that CCK acts at CCK-A receptors to produce satiety during the dark period in ad lib-feeding rats.     

Satiety, hunger and regional brain content of cholecystokinin/gastrin and met-enkephalin immunoreactivity in sheep

Cholecystokinin (CCK) and met-enkephalin (MEK) related peptides have been shown to alter feeding behavior subsequent to their injection into the peripheral circulation or directly into the brains of several species. To evaluate the potential role of endogenous brain pools of these peptides in feeding, groups of sheep were sacrificed either immediately following a meal (satiated) or after various intervals of food deprivation (hungry). Content of CCK-gastrin immunoreactivity in the anterior hypothalami of satiated sheep was elevated compared to 2, 4, or 24 hours of food deprivation. Content of MEK increased progressively with longer intervals of fasting (4 and 24 hours) in the amygdala and basomedial hypothalamus, whereas olfactory bulb content decreased with a similar time course. The results support a potential role for anterior hypothalamic CCK/gastrin in behaviors of satiety, whereas MEK neurons of limbic/rhinencephalic regions appear to form part of a separate circuit gradually activated by increasing hunger. Results are discussed in terms of potential target regions of the peptides, as well as the regional levels and feeding response of sheep as compared to available data from other species.     

Inhibition of satiety by a cholecystokinin antagonist is independent of gastric emptying

The ability of a cholecystokinin antagonist Proglumide to inhibit satiety induced by intraperitoneal injections of cholecystokinin octapeptide (CCK-OP) and bombesin was examined in rats equipped with chronic gastric cannulae. Both CCK-OP and bombesin significantly suppressed sham feeding. Proglumide administered alone did not alter sham feeding but it abolished the suppression of feeding induced by CCK-OP. In contrast, Proglumide did not inhibit the effect of a low dose of bombesin, but partially inhibited satiety induced by a high dose of bombesin, thus confirming our previous findings. These results indicate that the effect of Proglumide is independent of its recently described effects on gastric emptying in rat.     

Nucleus tractus solitarius lesions block the behavioral actions of cholecystokinin

Cholecystokinin (CCK) has been implicated as a signal for the syndrome of satiety in a variety of species. Several lines of evidence point to a peripheral site of action for the behavioral effects of CCK. Peripheral CCK receptors appear to activate a gut-brain pathway involving the sensory fibers of the vagus nerve. To investigate the central anatomical substrate of this visceral-behavioral control system, the terminal regions of the sensory tract of the vagus were lesioned. Radiofrequency lesions of the nucleus tractus solitarius abolished the effects of acute doses of CCK on exploratory behaviors. Sham lesions had no effect on baseline exploratory behaviors and did not influence the ability of CCK to decrease spontaneous exploratory behaviors. These findings delineate the first central site along the ascending sensory pathway which appears to mediate the satiety-related behavioral effects of CCK.     

Cholecystokinin and bombesin effects on rewarded and nonrewarded operants

Rats were food-rationed (15 g/day) and trained to bar-press for food. In Experiment 1, the animals were injected with cholecystokinin octapeptide (CCK, 2 μg/kg), bombesin (BBS, 12 μg/kg), normal saline, or prefed with 20 Noyes 45 mg pellets. The animals were then tested for one hour for bar-pressing responses with food reward. In Experiment 2, the animals were similarly trained, treated, and tested for bar-pressing responses without food reward. The results showed that BBS and prefeeding decreased bar-pressing, rewarded or non-rewarded, but the CCK effect was greatly decreased when food was withheld. It appeared that the CCK effect was more dependent upon the presence of food than the BBS or prefeeding effects. The results were discussed in terms of involvement of the food and reward-related oropharyngeal stimuli for the CCK effect and the drive-related stimuli for the BBS and prefeeding effects.     

Eating, drinking and temperature responses to intracerebroventricular cholecystokinin in the chick

The central effect of cholecystokinin-octapeptide (CCK), SQ 19,844 or sincalide, on the intake of food and water and on colonic temperature (Tc) was investigated using the broiler cockerel. Four-week old chicks were maintained in a thermoneutral environment of 23-24 degrees C. After food was removed for a 24 hr interval, CCK was infused in a volume of 10.0 microliters into the lateral cerebral ventricle (ICV) in doses ranging from 10-150 ng. Although lower doses of CCK had no effect on food intake, 100 or 150 ng of CCK significantly reduced consumption of food in a dose-dependent manner; water drinking was significantly decreased by 100 ng of CCK. In addition, CCK at doses of 100 and 150 ng prevented the slow rise in Tc observed following infusions of control CSF. This latter effect appeared to be a result of feeding activity associated with caloric intake and the heat increment in the control birds rather than a specific thermoregulatory effect. Overall, our results suggest that CCK may comprise a part of the central mechanism underlying the neural control of short term satiety in an avian species similar to that proposed for the mammal.     

Cholecystokinin and bombesin act independently to decrease food intake in the rat

The satiating effects of cholecystokinin-octapeptide (CCK-8) and bombesin (BBS) when injected alone and in combination were compared in intact rats. When injected alone, both CCK-8 and BBS elicited a dose-related decrease of 30-minute food intake. Injections of BBS were less potent than the equivalent doses of CCK-8 in producing satiety. BBS reached an asymptotic level of suppression of approximately 40 percent at a dose of 2 micrograms/kg, whereas injections of 4 micrograms/kg of CCK-8 resulted in a 72 percent suppression of food intake. When the two peptides were administered in a single injection, the resulting suppression of food intake was equivalent to that which would be predicted if their effects were completely additive. These results support the hypothesis that CCK-8 and BBS act via independent mechanisms to induce satiety. A preliminary model of peptidergic satiety, based on this hypothesis, is proposed.     

Abdominal vagotomy does not block the satiety effect of bombesin in the rat

Bombesin (2-16 microgram-kg-1, intraperitoneally) inhibited food intake in rats after abdominal vagotomy. Since the same vagotomized rats did not respond to the octapeptide of cholecystokinin (1-8 micrograms-kg-1, intraperitoneally), these data are decisive evidence (1) that bombesin does not produce satiety by releasing endogenous cholecystokinin and (2) that vagal afferents are not necessary for the satiety effect of bombesin.     

Dose-dependent effects of peptide YY(3-36) on conditioned taste aversion in rats

We used a conditioned taste aversion test to assess whether PYY(3-36) reduces food intake by producing malaise. Two-hour IV infusion of PYY(3-36) (8, 15, and 30 pmol/kg/min) at dark onset in non-food-deprived rats produced a dose-dependent inhibition of feeding and a conditioned aversion to the flavored chow paired with PYY(3-36) infusion. In food-deprived rats, PYY(3-36) at 2 and 4 pmol/kg/min inhibited intake of a flavored saccharin solution without producing conditioned taste aversion, whereas higher doses (8 and 15 pmol/kg/min) inhibited saccharin intake and produced taste aversion. These results suggest that anorexic doses of PYY(3-36) may produce a dose-dependent malaise in rats, which is similar to that reported for PYY(3-36) infusion in humans. Previous studies have shown that PYY(3-36) potently inhibits gastric emptying, and that gut distention can produce a conditioned taste aversion. Thus, PYY(3-36) may produce conditioned taste aversion in part by slowing gastric emptying.     

Effect of dietary fibre type on physical activity and behaviour in kennelled dogs

Dog diets may differ in their effectiveness of maintaining satiety after a meal. Consequently, sensations of hunger, feeding motivation, physical activity, and sensitivity to environmental stressors may be increased. Dietary fibre may be effective in prolonging postprandial satiety depending on type and inclusion level. This study evaluated the effect of fibre fermentability on behaviour in dogs. Sixteen healthy adult dogs were housed individually and fed a low-fermentable fibre (LFF) diet containing 8.5% cellulose or a high-fermentable fibre (HFF) diet containing 8.5% sugar beet pulp and 2% inulin. Dogs were fed two equal portions at 8:30 and 18:30 according to energy requirements. Behaviour of dogs in their home-cage was recorded and analyzed by instantaneous scan sampling (2 × 24 h with 15 min intervals) and focal sampling continuous recordings (10 min per animal per hour, from 9:00 until 18:00). Dogs were subjected to a behaviour test composed of the subtests open-field, sudden-silence, novel-object, and acoustic-startle. The behavioural responses of each dog were recorded. Scores for the scan and focal samples were expressed per clock hour and DIET × TIME effects were tested statistically using Residual Maximum Likelihood (REML). Data from the tests were examined using principal component analysis resulting in the compilation of two components. Data were tested statistically for DIET and DIET × SUBTEST effects using REML. Variables specific for the open-field and novel-object test were analyzed using analysis of variance. For the scans, a significant DIET × TIME effect was found for resting. At night and in the morning, HFF dogs rested more compared to LFF dogs, but they rested less between 14:00 and 17:00. For the continuous recordings, the main findings were a tendency for DIET × TIME effect for time spent resting with a pattern consistent with that for the scans. The interaction was significant for inactive-alert (lie with head up or sitting) with HFF-fed dogs having lower values around 10:00–11:00 and higher values hereafter. Finally, time spent tail wagging was significantly higher for LFF-fed dogs just before the evening meal that may indicate higher level of arousal. For the behaviour tests, no significant DIET or DIET × SUBTEST effects were detected. It is concluded that compared to the LFF diet, the HFF diet increased inactivity in kennelled beagle dogs likely through the prolongation of postprandial satiety. This effect did not change the reaction to stressful events in kennelled laboratory dogs. Enhanced susceptibility to environmental stressors at times of hunger in sensitive companion dogs may occur but requires further study.