Search

Intestinal infusion of nutrients, such as glucose and oleic acid, increase Fos-like immunoreactivity (Fos-LI) in both the enteric nervous system and neurons of the dorsal vagal complex (DVC) of the hindbrain. To test the hypothesis that increased Fos-LI in enteric neurons and the DVC, following intestinal nutrient infusions is mediated by cholecystokinin(1) receptors (CCK(1)), we counted enteric and DVC neurons that expressed Fos-LI following intestinal infusion of oleate or glucose, with and without pretreatment with the CCK(1) receptor antagonist, lorglumide. Both oleate and glucose infusions increased Fos-LI in the DVC. Oleate also increased Fos-LI in the myenteric and submucosal plexuses of the duodenum and the jejunum, but not the ileum, while glucose only increased Fos-LI in the submucosal plexus of the ileum. The CCK(1) receptor antagonist, lorglumide, abolished Fos-LI in the DVC following infusions of either oleate or glucose. In addition, lorglumide attenuated oleate-induced Fos-LI in the myenteric and submucosal plexuses of the duodenum and jejunum. However, lorglumide failed to attenuate glucose-induced Fos-LI in the submucosal plexus of the ileum. These data confirm previous reports indicating that CCK(1) receptors mediate increased DVC Fos-LI following intestinal infusion of oleate or glucose. CCK(1) receptors also contribute to increased Fos-LI in enteric neurons following intestinal oleate infusion. However, failure of lorglumide to attenuate the increase of Fos-LI in the ileal submucosal plexus following intestinal glucose suggests that some intestinal nutrients trigger Fos-LI induction via CCK(1) receptor-independent pathways.

Otsuka Long-Evans Tokushima Fatty (OLETF) rat lacking CCK-A receptors are hyperphagic and obese. Previous work has demonstrated alterations in neuropeptide Y (NPY) and proopiomelanocortin (POMC) mRNA expression in ad libitum fed OLETF rats compared to lean Long-Evans Tokushima Otsuka (LETO) controls. In order to determine whether alterations in sensitivity to central peptides involved in overall feeding control may contribute to the hyperphagia and obesity in OLETF rats, we assessed OLETF and LETO rats feeding responses to lateral ventricular infusions of NPY (1 and 3.2 nmol), the melanocortin 3/4 agonist MTII (0.1 and 0.32 nmol) and the melanocortin receptor antagonist SHU-9119 (0.25 and 0.5 nmol). At a 3-h time point, NPY increased food intake in both OLETF and LETO rats. OLETF rats were more sensitive, having significant increases at both NPY doses and a greater increase at the higher dose. The melanocortin agonist MTII decreased intake in both LETO and OLETF rats. At the 20-h time point, the magnitude of suppression was greater in OLETF rats. SHU-9119 increased food intake in both groups. OLETF rats were more sensitive with larger relative increase and longer-lasting effects at the lower dose. These results are consistent with demonstrated alterations in neuropeptide gene expression in OLETF rats and indicate that alterations in responsivity to NPY and melanocortin signaling are unlikely to contribute to their hyperphagia and obesity.

Cholecystokinin (CCK) is deeply involved in the control of learning and emotional behaviors. The authors characterize the behavioral properties of Otsuka Long Evans Tokushima Fatty (OLETF) rats, which lack the CCK-A receptor because of a genetic abnormality. In the Morris water-maze task, the OLETF rats showed an impaired spatial memory. In the inhibitory avoidance test, they showed facilitating response 24 h after training. Hypoalgesia was observed in a hot-plate test. In the elevated plus-maze and food neophobia test, OLETF rats showed an anxiety-like response. In addition, OLETF rats were hypoactive in the Morris water-maze and the elevated plus-maze. The results suggest that the OLETF rats showed a spatial memory deficit, hypoactivity and anxiety due, at least in part, to the lack of CCK-A receptors.

Because of a genetic mutation, the Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat, a model for human non-insulin-dependent diabetes mellitus (NIDDM), shows no expression of the CCK-A receptor gene. We investigated the spontaneous physical activity, sleep, and body temperature in young OLETF rats that had not yet developed diabetes mellitus, and compared these data with age-matched control LETO (non-diabetic strain, Long-Evans-Tokushima-Otsuka) rats. The amount of large movements during the dark phase for the OLETF rats was significantly less than that of control rats. Thus, the amounts of total daily large movement and the ratio of dark-to-light phase movement in the OLETF rats were less than those of control rats, although the amount of small movement was similar for both groups. The diurnal rhythm of body temperature was similar for both groups. In addition, the amount of and circadian rhythm for each vigilance state and slow-wave activity were similar for the two groups. This study demonstrates that the CCK-A receptor might play a role in affecting the level of motor activity, adding hyperphagia, and the circadian rhythm of large movement in these rats prior to the manifestation of NIDDM. In contrast, a CCK-A receptor deficiency does not appear to affect sleep or body temperature in these rats.

Cholecystokinin (CCK) is one of the most abundant neurotransmitter peptides in the brain. As OLETF rats lack CCK-A receptor because of a genetic abnormality, we examined whether learning and memory were impaired in these animals using an elevated eight-arm radial maze. After the completion of a radial maze study, the animals were sacrificed for histological examination of the brain. In some animals, long-term potentiation (LTP) in the hippocampus was measured. In the radial maze, the level of activity (seconds/entry) and the time remaining in the arms were significantly longer in OLETF rats. The number of errors was also significantly higher, and that of the correct choices was significantly lower in OLETF rats compared to the controls (LETO rats). The LTP of the population spike was significantly lower in the OLETF than in the LETO rats. No histological abnormalities were observed. From these observations, we concluded that learning and memory functions were impaired in the OLETF rats.

Systemic injections of cholecystokinin octapeptide sulfate ester (CCK-8-SE) elicit various behavioral and autonomic responses, such as increases in nonrapid-eye-movement sleep (NREMS) and hypothermia. There are two CCK receptors; both CCK-A and CCK-B receptors are stimulated by CCK-8-SE. The relative importance of the CCK-A and CCK-B receptors in the somnogenic and hypothermic effects of CCK-8-SE is not well understood. In the present experiments, we studied the effects of the selective activation of CCK-B receptors by CCK tetrapeptide (CCK-4) or nonsulfated CCK-8 (CCK-8-NS) on sleep and brain temperature (Tbr). Rats were injected intraperitoneally with saline on the control day and with CCK-8-NS (10, 50, or 250 microg/kg) or CCK-4 (10, 50, or 250 microg/kg) on the test day 5-10 min before dark onset. Electroencephalogram, electromyogram, and Tbr were recorded for 12 h. None of the treatments affected sleep or Tbr significantly, with the exception of 10 microg/kg CCK-4, which transiently decreased the amount of NREMS, and 10 microg/kg CCK-8-NS, which slightly increased REMS. These results suggest that the activation of CCK-B receptors by systemic injection of CCK-4 or CCK-8-NS is not sufficient to elicit increased NREMS and hypothermia in rats.

The genetically obese Zucker rat (fa/fa) is hyperphagic compared to lean controls (Fa/?). This hyperphagia is characterized by increased meal size. Cholecystokinin (CCK) has been shown to decrease meal size in many species including humans. In the present study we investigated the role of endogenous CCK in mediating the hyperphagia of male and female obese Zucker rats. CCKA-type receptors were blocked with the specific antagonist, devazepide, and test meal size was measured. Male obese and lean rats significantly increased food intake following devazepide. Neither obese nor lean female rats significantly increased food intake following devazepide. This is the first demonstration of a gender difference in endogenous CCK-mediated satiety. These results have implications for the higher incidence of eating disorders in females.

Pigs have a strong appetite for sugar solutions and readily learn to perform operant responses (pressing a panel with their snouts) to obtain glucose solution. Intracerebroventricular (ICV) injection of 1 microgram CCK produced a significant (p < 0.01) reduction in the amount of glucose consumed compared with saline in the 30 min following injection. The reduction was a central effect as the same dose of CCK was ineffective given intravenously. The inhibition of intake was completely abolished by prior dosing with 100 micrograms of the CCKA receptor antagonist Devazepide given ICV. Devazepide itself had no effect on intake. The pig is a good experimental animal for the study of the regulation of sugar intake.

The satiety effects of the hormone, cholecystokinin (CCK), and propionate, an important gluconeogenic substrate, were studied in ad lib-fed sheep. Hepatic portal infusion of either sodium propionate (1.2 mmol/min) or sulphated CCK-8 (sCCK-8; 18.3 pmol/kg/min) had no effect on food intake. However, together, they decreased intake by 44%; similar to the effect of 2.4 mmol/min propionate alone. CCK infusions reduced the frequency of reticular contractions in the presence or absence of propionate. The effects of infusions on motility and food intake were, therefore, dissociated. Further studies demonstrated axonal transport of CCK binding sites in the ovine vagus. Binding sites accumulated to a similar extent on both sides of a ligature indicating the existence of both anterograde and retrograde transport which was limited to a small proportion of fibres. Binding incubations carried out in the presence of the CCK receptor antagonists, MK-329 and L-365,260, indicated that the majority of binding sites, if not the total population, possessed pharmacology typical of type B CCK receptors.

Anorexia is a common response to infection which is thought to be mediated, at least in part, by interleukin (IL-1), an immunoregulatory peptide secreted by activated monocytes. Cholecystokinin (CCK) is a neuropeptide that suppresses food intake and gastric emptying when injected into healthy animals. There is increasing evidence of bidirectional interactions between neuropeptides, immune cell function, and secretion of immunoregulatory cytokines. Therefore, the present study was undertaken to determine if administration of L364,718 (L364), a CCK receptor antagonist, might block the anorexigenic effects of recombinant human IL-1 alpha (IL-1 alpha) in rats. We report that injection of IL-1 alpha significantly increased plasma CCK 1 h after injection, and decreased food intake and emptying of gastric contents. Pretreatment with 1 mg/kg L364 partially blocked the decrease in food intake and gastric stasis induced by IL-1 alpha. We conclude CCK may mediate, at least in part, IL-1 alpha-induced anorexia.

The ability of nanomolar concentrations of guanine, but not adenine, nucleotides to inhibit specific 125I-Bolton-Hunter CCK binding to ligated rat vagus nerve demonstrated that vagal CCK binding sites were linked to G-proteins during axonal transport. The GTP analogue, GTP[S], reduced specific binding to both anterogradely and retrogradely transported binding sites by more than 90% at 1 microM. Transport of these putative receptor-G-protein complexes was examined under conditions of food deprivation or physiological hyperphagia induced by either lactation or genetic obesity. None of the physiological or imposed manipulations of food intake had any effect on the axonal transport of CCK binding sites. Transection of the cervical vagus resulted in an accumulation of binding sites at the lesion site that was indistinguishable from that seen following ligation for the same period.

Data obtained from a wide variety of mammalian species indicate that feeding behavior can be influenced by changes in endogenous estrogens and by exogenous estrogenic treatments. The present experiment represents an initial investigation of the hypothesis that the suppression of food intake by estradiol is mediated by an enhancement of the satiety effect of cholecystokinin (CCK). Twenty-four female rats were ovariectomized and implanted either with a 5% estradiol silastic capsule or an empty capsule on the day of surgery. Three weeks later, animals received IP injections of CCK-octapeptide (5.0 or 10.0 micrograms/kg) or saline after 24-h food deprivation. Food and water intake were measured 60 min after treatment. Although CCK suppressed feeding in all subjects, the effects on food intake were greater in estradiol-treated females. CCK injections also reduced water intake, but there was no interaction between estradiol and CCK on drinking. These findings indicate that the inhibitory effect of CCK on food intake is enhanced in females treated with a physiological dose of estradiol, and suggest that the effects of estradiol on feeding behavior may be mediated by a potentiation of the satiety effect of CCK.

Operant feeding was recorded in 18 h deprived pigs after peripheral (IV) or central (ICV) administration of saline, the CCK A agonist A-71378, the CCK B agonist pentagastrin, or pentagastrin vehicle. In Experiment 1 (n = 10), A-71378 (0.5, 1.0, and 2.0 micrograms/kg) given IV produced a sustained dose-related reduction in food intake (p < 0.02), whereas the same doses of pentagastrin were without effect. In Experiment 2 (n = 10), neither agonist given ICV (1 microgram) had consistent effects on operant responding. A higher ICV dose of A-71378 (5 micrograms) was also ineffective, whereas 1 microgram CCK octapeptide given ICV inhibited feeding (p < 0.03). These findings suggest that A receptors outside the blood-brain barrier mediate the suppressant effect of IV CCK on feeding in the pig and that neither peripheral nor central B receptors influence food intake in this species.

The effect of dietary medium chain triglyceride (MCT) on short-term food intake was compared with the effect of long chain triglyceride (LCT) in rats. Corn oil and glyceryl tricaprylate were used as LCT and MCT sources, respectively. Rats were given diets containing 200 g MCT/kg diet (MCT diet), 100 g MCT + 100 g LCT/kg diet (ML diet), or 200 g LCT/kg diet (LCT diet) in Experiment 1. Cumulative food intake was determined every h for the first 12 h, then at 2-h intervals thereafter during the subsequent 12 h. As early as 1 h after feeding, cumulative food intake significantly decreased in MCT-fed animals in a dose-dependent fashion. In Experiment 2, rats were given a choice between MCT and LCT diets for 1 h to confirm whether or not the palatability of diets was influenced by dietary fat sources. There was no difference in food intake between the two diets. In Experiment 3, the responsibility of endogenous cholecystokinin (CCK) for the difference in food intake between the two diets was investigated for 6 h by using a CCK-A receptor antagonist, Devazepide (DVZ, 1 mg/kg b. wt.). Food intake in the MCT diet and also in the LCT diet was improved by DVZ. It is concluded that the satiety, but not the palatability, is affected by carbon chain length in dietary triglyceride sources, although the responsibility of endogenous CCK is very small.

To assess the role of cholecystokinin (CCK) receptors in mediating the satiating effect of an oral preload, overnight food-deprived rats (n = 7) were given access to a high-carbohydrate liquid diet for 40 min. At the end of 40 min, food was removed and rats were injected subcutaneously (SC) with devazepide (DVZ; 1 ng/kg-1 mg/kg), an antagonist selective for the CCK-A receptor, or its vehicle, 0.5% carboxymethylcellulose (CMC). Thirty min after injection, rats were given access to the same liquid food for 60 min. DVZ increased food intake significantly. Furthermore, the effectiveness of a very low dose of DVZ (10 ng/kg) is strong evidence that the effect of DVZ was specific for CCK-A receptors. Three of the rats that increased food intake after DVZ were also tested with L-365,260, an antagonist selective for the CCK-B receptor (10 ng/kg-100 micrograms/kg). L365,260 did not increase food intake significantly. These results confirm and extend previous reports that CCK-A receptor blockade increases food intake after an oral preload. They do not, however, demonstrate a role for the CCK-B receptor in mediating the satiating effect of ingested food under the same experimental conditions.

Almost two decades ago, exogenous cholecystokinin (CCK) was shown to suppress food consumption in rats. Since then, CCK has been detected not only in peripheral tissue but extensively throughout the central nervous system. Furthermore, specific CCK receptors have been described, and a distinction drawn between CCK-A and CCK-B receptors. Recently, potent, orally active CCK antagonists, which show a high degree of selectivity for either CCK-A or CCK-B receptors, have been introduced. The present report reviews recent evidence obtained in studies using devazepide (a selective CCK-A receptor antagonist) and L-365,260 (a selective CCK-B/gastrin receptor antagonist). Both compounds increased food consumption and postponed the onset of satiety in well-satiated rats. L-365,260 was more potent, suggesting that central CCK-B type receptors may mediate the satiety effects of endogenously released CCK. Only devazepide was effective in blocking the feeding-suppressant effect of exogenous CCK, indicating that CCK-A type receptors mediate this effect. In a second series of studies, devazepide but not L-365,260 antagonized the anorectic effect of either d-fenfluramine or systemically administered 5-HT. Hence, CCK-A type receptors appear to be involved in the anorectic effects of these serotonergic drugs. We propose that CCK and 5-HT mechanisms involved in mediating satiety are mutually interdependent. Possible interactions between CCK and catecholaminergic mechanisms are also briefly considered.

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.