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PubMed1998

An evaluation of the influence of devazepide and CCK-8S on the intact and resected rat liver.

BACKGROUND: Recently, it has been shown that infusion of the CCK-A receptor antagonist devazepide induced proliferation of hepatocytes and bile duct epithelium in the rat liver. The aim of this study was to further evaluate the influence of devazepide and sulfated cholecystokinin-8 (CCK-8S) on the intact rat liver and rat liver after resection. METHODS: In the first experiment, either saline or devazepide was injected subcutaneously twice daily to rats for 18 and 36 h and 3 and 7 days. In the second experiment, a 70% liver resection was followed by infusion of either DMSO, devazepide, saline or CCK-8S for 2 or 7 days. Prior to sacrifice, all rats received 1 mCi/kg of tritiated thymidine intraperitoneally. The liver was excised and the contents of protein, DNA and water and incorporation of tritiated thymidine were measured. RESULTS: Intermittent injections of devazepide increased the liver protein content after 36 h, followed by a decrease after 7 days. The weight, DNA content or cell proliferation was not affected. Two days after liver resection hyperCCKemia was evoked, which was less prominent after 7 days. Devazepide lowered the plasma concentration of CCK, while the infusion of CCK-8S resulted in extremely high concentrations at both time points. The DNA synthesis measured by thymidine incorporation was increased by devazepide on day 2, whereas the weight or protein and DNA contents of the liver were not influenced. CCK-8S infusion decreased the body and liver weight throughout the study, and the protein and DNA contents after 7 days. CONCLUSIONS: Intermittent devazepide treatment did not affect the intact liver. Devazepide increased the DNA synthesis 2 days after liver resection but was without other influences on the liver regeneration. CCK-8S induced decreased body weight with ensuing negative effects on the liver regeneration. Neither devazepide nor CCK seem to be of any therapeutic use after liver resection or liver failure.

Animals↗

PubMed1998

The effect of intermittent injections of CCK-8S and the CCK-A receptor antagonist devazepide on cell proliferation in exocrine rat pancreas.

CONCLUSION: Intermittent injections of sulfated cholecystokinin-8 (CCK-8S) or devazepide caused long-lasting effects on cell proliferation in exocrine pancreas in contrast to continuous infusion. The acinar cells responded to both treatments with changes in the labeling index (LI) during the whole study period. When studying the influence of stimulation and inhibition of the CCK-A receptor on cell proliferation in the exocrine pancreas, not only are the drugs and doses of importance but also the mode of administration. BACKGROUND: Continuous infusion of CCK-8S or the CCK-A receptor antagonist devazepide induces transient changes in acinar cell proliferation in rat pancreas. The aim of the present experiments was to study whether intermittent administration of CCK-8S or devazepide prevents receptor desensitization and thereby affects exocrine pancreatic cell proliferation persistently. METHODS: Male Sprague-Dawley rats were injected subcutaneously twice daily with CCK-8S (6 micrograms), devazepide (240 micrograms) or bovine serum albumin (BSA). The rats were sacrificed after 18 and 36 h and 3 and 7 d. One hour before sacrifice, the rats were injected intraperitoneally with 1 mCi/kg of tritiated thymidine. The pancreatic weight and the contents of water, protein, and DNA were determined. The LI (number of labeled cells/100 cells) of exocrine pancreatic cells was determined microscopically after autoradiography. RESULTS: The concentration of plasma CCK was slightly increased by devazepide, but the increase was more pronounced by CCK-8S. The pancreatic wet weight was transiently increased 18 h after the start of CCK-8S injections (+14%), whereas devazepide caused a reduction after 7 d (-22%). The protein content was uninfluenced and the DNA content was decreased at 36 h with either treatment. CCK-8S increased the LI in acinar and centroacinar cells throughout the study period, but the ductal cell LI was increased only after 18 and 36 h. Injection of devazepide was followed by decreased LI of acinar cells throughout the study period. Also, the centroacinar and ductal cell LI decreased initially but returned to control values after 7 d.

Animals↗

PubMed1996

Devazepide, a CCKA receptor antagonist, impairs the acquisition of conditioned reward and conditioned activity.

Cholecystokinin (CCK) is co-localized with dopamine (DA) in portions of the mesolimbic system, where it may facilitate the function of DA through the CCKA receptor subtype. DA has been implicated in the acquisition of conditioned incentive learning, raising the possibility of a role for endogenous CCK in this learning process. This hypothesis was tested using two complementary behavioral paradigms. Experiment 1 examined the effects of systemic administration of the CCKA receptor selective antagonist, devazepide (0, 0.001, 0.01, 0.1 mg/kg), on the acquisition of conditioned reward. Two novel levers were presented to drug-free animals in a test session; depression of the conditioned reward (CR) lever produced a light-tone stimulus previously paired with food availability while depression of the non-CR lever produced no programmed consequence. Animals receiving vehicle pretreatment in the food-CS conditioning sessions responded more frequently on the CR lever during the test session. However, pre-treatment with devazepide (0.1 mg/kg but not 0.001 or 0.01 mg/kg) in the conditioning sessions blocked the acquisition of conditioned reward. In contrast, experiment 2 showed that the development of conditioned reward was not affected by similar administration of the CCKB selective antagonist, L-365,260 (0, 0.001, 0.01, or 0.1 mg/kg). The possibilities that devazepide (0.1 mg/kg) impaired the development of conditioned reward by decreasing the amount of food consumed or by inducing a conditioned taste aversion to the food were ruled out in experiments 3 and 4. The effects of devazepide on the acquisition of conditioned activity induced by amphetamine were assessed in experiment 5. During four conditioning sessions, rats received devazepide (0, 0.001, 0.01, 0.1 or 1.0 mg/kg) treatment prior to amphetamine-environment pairings. The conditioned activity effect was demonstrated if on the subsequent drug-free test day the environment alone elicited increased locomotion. Devazepide (0.1 or 1.0 mg/kg) attenuated the development of conditioned activity. Together, these results provide converging evidence that intact CCKA function may be necessary for the development of conditioned incentive learning.

Animals↗

PubMed1993

Effects of diet and the cholecystokinin antagonist; devazepide (L364,718) on CCK mRNA, and tissue and plasma CCK concentrations.

The mechanisms by which raw soya diets and CCK-receptor antagonists increase postprandial plasma CCK concentrations are not fully understood. Therefore we examined the effects of different diets including raw soya, and the effect of the potent CCK antagonist devazepide in the fed and fasted state on CCK concentrations in plasma and in the duodenal mucosa and on the duodenal CCK:beta-tubulin mRNA ratio in rats. Diets which stimulated high plasma CCK levels, such as raw soya, also gave the highest CCK tissue and mRNA concentrations with a close correlation between plasma and tissue CCK concentrations within each group (r = 0.94, P = 0.018) and between tissue CCK concentrations and CCK:beta-tubulin mRNA ratios (r = 0.91, P = 0.030). Animals fed ad libitum and treated with devazepide (1 mg kg-1) had higher CCK:beta-tubulin mRNA ratios, tissue CCK concentrations and plasma CCK concentrations than animals injected with vehicle. Fasted animals treated with devazepide for 28 h also had higher CCK mRNA:beta-tubulin mRNA ratios (1.86 +/- 0.43 vs. 0.85 +/- 0.15, P < 0.05), and higher tissue CCK concentrations (0.99 +/- 0.09 vs. 0.69 +/- 0.04, P < 0.01). However, despite these intracellular changes devazepide did not elevate plasma CCK concentrations in the fasted state. Therefore, devazepide increases tissue concentrations of CCK but requires an additional dietary stimulus to raise plasma concentrations. These findings indicate that devazepide produces a dissociation between synthesis and release of CCK in fasted animals.

Animals↗

PubMed1999

Relative blood-brain barrier permeabilities of the cholecystokinin receptor antagonists devazepide and A-65186 in rats.

The blood-brain barrier permeabilities of the type-A cholecystokinin receptor antagonists devazepide and A-65186 (Nalpha-3-quinolinoyl-D-Glu-N,N-dipentylamide) have been compared with those of the reference compounds iodoantipyrine, which readily penetrates the blood-brain barrier, and mannitol, which does not. Anaesthetized rats received a bolus injection into the left carotid artery of [14C]iodoantipyrine (0.25 microCi) combined with [3H]mannitol, [3H]devazepide or [3H]A-65186 (1 microCi each). Rats were decapitated 12s after injection and the brains were removed. Four samples of left cerebrum (ca 100 mg each) were solubilized overnight and 14C and 3H activity were measured. The brain-uptake index for each test compound was determined as [(3H/l4C for sample)]/[(3H/14C for injectate)] x 100, with a value of 100 representing blood-brain barrier permeability equal to that for iodoantipyrine. The brain-uptake index (mean+/-s.e.m.) was 1.6+/-0.3 for [3H]mannitol (n=5), 90.6+/-4.1 for [3H]devazepide (n=7, P<0.001 compared with mannitol) and 3.5+/-0.7 for [3H]A-65186 (n=4, P > 0.05 compared with mannitol, P < 0.001 compared with devazepide). Thus, devazepide readily penetrated the blood-brain barrier whereas A-65186 did not. It is concluded that devazepide and A-65186 are likely to be useful pharmacological tools for determining whether cholecystokinin is acting peripherally or at brain sites beyond the blood-brain barrier to produce satiety or any other function mediated by the type A cholecystokinin receptor.

Anesthesia↗

PubMed1994

The CCKA receptor antagonist devazepide does not modify opioid self-administration or drug discrimination: comparison with the dopamine antagonist haloperidol.

We previously reported that the selective cholecystokininA (CCKA) receptor antagonist, devazepide, blocked the acquisition of a morphine conditioned place preference (ref 28). An interpretation of this finding is that devazepide may either affect an opioid discriminative stimulus and/or modify the rewarding properties of opioids. The present study was designed to investigate these issues by determining the effect of equivalent doses of devazepide in a morphine drug discrimination paradigm and a model of heroin self-administration. In each case, devazepide (0.001-1 mg/kg) was ineffective, i.e there was no antagonism of a morphine discriminative cue, and in a separate group of rats trained to self-administer heroin (0.03 mg/kg/infusion, FR5 schedule, 1h per day), devazepide did not alter the pattern of heroin responding. Because of evidence implicating an interaction between accumbens CCK and dopamine (DA) systems and evidence suggesting an apparent differential involvement of DA in opioid place conditioning, self-administration and drug discrimination behaviour, the effect of the DA antagonist haloperidol was examined in the latter two paradigms. In each test, haloperidol produced an effect inconsistent with a direct DAergic involvement. In a final study the CCKB antagonist L365-260 was also found not to affect an opioid discriminative cue. The present results therefore cast doubt on the potential utility of selective CCKA antagonists as treatments for opioid abuse, and further suggest that CCKB antagonists may not potentiate the subjective effects of opioids, an important finding considering that such drugs have been proposed as adjuncts to opioid therapy for the treatment of pain relief.

Animals↗

PubMed1994

Devazepide alters meal patterns in lean, but not obese, male Zucker rats.

Meal patterns were recorded for 10.5 h in six lean and eight obese adult male Zucker rats after treatment with the cholecystokinin type A (CCKA) receptor antagonist, devazepide (750 micrograms/kg, IP, at 1330 h) or vehicle. In lean rats, devazepide significantly increased total food intake by 11%, average meal size by 35%, and meal duration by 49%. Devazepide also significantly decreased the average number of meals by 18%, although this was a smaller effect. Devazepide had none of these effects in obese rats. Devazepide treatment altered the meal pattern of lean rats so that it was similar to that of obese rats. These results demonstrate that endogenous CCK has a satiating effect in lean, but not in obese, male Zucker rats, which is the first demonstration of a loss of a physiological satiety signal in the obese Zucker rat. This defect could be due to: 1) a decrease in the release of endogenous CCK, 2) a decrease in the rate of CCK synthesis, or 3) the production of an abnormal form of CCK.

Animals↗

PubMed1992

The CCK-A and CCK-B receptor antagonists, devazepide and L-365,260, enhance morphine antinociception only in non-acclimated rats exposed to a novel environment.

Devazepide, a potent CCK-A receptor antagonist, and L-365,260, a selective CCK-B receptor antagonist, have been introduced as pharmacologic tools for differentiating the physiologic roles of CCK-A and CCK-B receptor subtypes. In the present study, we tested the effects of devazepide and L-365,260, on morphine antinociception in rats using the thermal sensorimotor tail flick test. Both devazepide and L-365,260 significantly enhanced the antinociceptive action of morphine, but only in rats that had not been acclimated to the laboratory environment or habituated to investigator handling. When tested with fully acclimated animals, devazepide and L-365,260 had no effect whatsoever; they neither enhanced nor attenuated morphine-induced antinociception. These observations indicate that the effects of devazepide and L-365,260, CCK antagonists, on morphine antinociception appear to be dependent on the animal's response to a new environment or to the stress induced by an unaccustomed experimental paradigm.

Adaptation, Physiological↗

PubMed1993

Characterization of CCK receptors in a novel smooth muscle preparation from the guinea-pig stomach by use of the selective antagonists CI-988, L-365,260 and devazepide.

1. The cholecystokinin receptors mediating motor responses in a novel smooth muscle preparation from the corpus region of the guinea-pig stomach have been characterized by use of five agonist peptides and the antagonists CI-988, L-365,260 and devazepide. 2. Mucosa-denuded strips of circular muscle were contracted in a concentration-dependent manner by the five cholecystokinin (CCK)-related peptides CCK-8S, pentagastrin, gastrin-I, CCK-8US and CCK-4. 3. CI-988 was a powerful antagonist of the response to pentagastrin with an affinity (pKB = 9.49) similar to that obtained in CCKB receptor binding assays. With CCK-8S as the agonist, CI-988 was approximately 1000 fold less powerful as an antagonist. 4. Devazepide powerfully blocked responses to CCK-8S with an affinity (pKB = 9.54) that was in agreement with reported functional data obtained in pancreatic amylase secretion studies, a system exhibiting CCKA receptor activity. Devazepide displayed lower affinity against pentagastrin than against CCK-8S. 5. CI-988 blocked responses to pentagastrin in an insurmountable manner in the presence of 3 nM devazepide; a concentration previously shown to block the CCKA receptor. The nature of the antagonism observed with L-365,260 was unaltered by the presence of devazepide. 6. The guinea-pig stomach corpus smooth muscle preparation contains both subtypes of CCK receptor and will be useful as a pharmacological tool for investigating the functional effects of novel CCK ligands.

Animals↗

PubMed1993

The effect of the cholecystokinin antagonist devazepide (L364718) on the ileal brake mechanism in the rat.

Studies were carried out on 28 male adult rats to investigate whether the selective cholecystokinin-receptor antagonist devazepide influences gastrointestinal transit under control conditions and when it is delayed by ileal infusion of lipid. Stomach-to-caecum transit time of the head of the test meal was measured using environmental hydrogen analysis and the distribution of the meal was assessed using the radiolabelled meal technique. Oral administration of devazepide (4 mg kg-1) had no significant effect on transit time of the head of the baked bean test meal under control conditions, but significantly reversed the delay in transit time induced by ileal infusion of lipid (P < 0.01). Studying the distribution of the meal showed that Intralipid delayed transit time by delaying both gastric emptying (P < 0.01) and small bowel transit (P < 0.05). Devazepide did not alter the control distribution of the meal during ileal saline infusion, but during ileal infusion of lipid, devazepide further delayed gastric emptying (P < 0.01); the geometric centre of the meal was situated more proximally in the gastrointestinal tract (P < 0.05), but there was more of the meal in the colon (P < 0.01). The latter is compatible with the early rise in environmental hydrogen during devazepide administration and ileal lipid infusion and suggests that peripheral cholecystokinin receptors may modulate or mediate the delay in small bowel transit induced by ileal lipid. However, the data also suggest that mechanisms other than those involving cholecystokinin play a dominant role in the regulation of postprandial and lipid-delayed gastric emptying of a meal.

Animals↗

PubMedDate not supplied

Devazepide-induced hyperplasia in the rat liver and bile ducts.

Cholecystokinin (CCK) is a potent stimulus of pancreatic enzyme secretion and growth and is known to influence the flow of biliary secretions. It has also been suggested as a trophic stimulus of the biliary tract and liver, but confirmatory studies are lacking. The aim of the present experiment was to study the effects on the rat liver and biliary tract of long-term stimulation of CCK-8S and the CCK-A receptor antagonist devazepide, respectively. Sprague-Dawley male rats had an infusion of sulfated CCK-8, devazepide or sodium chloride by subcutaneously implanted osmotic minipumps. The animals were sacrified 36 h and 3, 7 or 28 days after the start of infusion, and all had an injection of tritiated thymidine (1 mCi/kg) intraperitoneally 1 h prior to death. The liver was dissected out, weighed and processed for its content of protein, DNA and water. After autoradiography, histologic samples were examined for labeled hepatocytes and bile duct epithelium. Devazepide caused an increase in liver protein content from 36 h on. After 3 days labeling index of hepatocytes and liver DNA concentration were increased. On day 7, induced cell proliferation was also seen in the bile duct epithelium, and the increase in liver DNA content and concentration was now more pronounced and persisted throughout the study. After 28 days devazepide also induced increased crude and relative liver weight. A transient reduction in liver weight and liver protein content and concentration was seen after 7 days of CCK-8S infusion. There were no changes of the labeling index of hepatocytes or bile duct epithelial cells or in liver DNA content in the rats receiving CCK-8S infusion. Devazepide induced hyperplastic changes in both the liver and the biliary tract, probably by interfering with the bile secretion, whereas CCK-8S did not exert any similar effects. The results do not support CCK as a hepatotrophic factor.

Animals↗

PubMed1990

The cholecystokinin receptor antagonist devazepide enhances morphine-induced analgesia but not morphine-induced respiratory depression in the squirrel monkey.

The effects of the cholecystokinin antagonist devazepide on analgesia and respiratory depression induced by morphine in squirrel monkeys were examined. Pain thresholds were determined using the tail withdrawal procedure, in which monkeys restrained in chairs kept their tails in cool (35 degrees C) water for at least 20 sec, but withdrew them from warm (55 degrees C) water in less than 4 sec. Morphine produced a dose-related increase in tail withdrawal latencies from warm water. Devazepide (injected i.p. or p.o.) had no effect on tail withdrawal latencies when given alone but enhanced the analgesic effects of morphine. The devazepide dose-response curve for morphine enhancement was bell-shaped with doses of 3, 10, 30 and 100 micrograms/kg injected i.p. increasing morphine analgesia whereas higher and lower dose did not. In a separate group of monkeys, morphine produced dose-dependent decreases in respiratory rate and oxygen tension and increases in carbon dioxide tension. In contrast to its effects on morphine analgesia, devazepide had no effect on the various indices of morphine-induced respiratory depression. These data suggest that devazepide may have therapeutic utility as an adjuvant to morphine analgesia allowing lower dose of the opiate to be used to relieve pain and reducing the risk of opiate-induced respiratory depression.

Administration, Oral↗

PubMed1996

Devazepide (L-364718) inhibits growth and increases expression of tumor markers in HT29-S-B6 cells.

Devazepide (L-364718, a non-peptide antagonist of CCK-A receptors), inhibits the proliferation and induces morphologic changes in the mucous-secreting, autonomously proliferating human cancer colon cell line (HT29-S-B6. Addition of devazepide (10 microM) for at least 3 days in the exponential phase of growth enhanced the baseline production of gastric M1 mucins 2-3-fold and that of carcinoembryonic antigens 5-fold. Moreover, devazepide induced an increase in the amount of the MUC-5AC mRNA expressed by HT29-S-B6 cells. The increased in mucins secretion induced by devazepide was persistent after removal and independent of the presence of serum. In conclusion, devazepide-L-364718 behaves as a maturation agent in the cell clone HT29-S-B6.

Benzodiazepinones↗

PubMed1998

Devazepide, a CCK(A) antagonist, attenuates the satiating but not the preference conditioning effects of intestinal carbohydrate infusions in rats.

Endogenous cholecystokinin (CCK) is thought to participate in the satiating action of foods, and some data suggest that it may also mediate their postingestive reinforcing effects. This was investigated by determining if the CCK(A) receptor antagonist, devazepide, attenuates flavor preference conditioning by intraduodenal (I.D.) carbohydrate infusions. In Experiment 1, food-restricted female rats were trained 30 min/day to associate a cue flavor (CS+) with I.D. infusions of 8% Polycose and a different flavor (CS ) with I.D. water infusions. Half of the rats (DEV group) were pretreated with devazepide (300 microg/kg body weight) and the other half (CON group) with vehicle, 30 min prior to CS training sessions and choice tests. Both groups displayed similar CS+ preferences (CON: 68%; DEV: 69%). In contrast, devazepide blocked the feeding inhibitory effects of I.D. Polycose infusion and cholecystokinin octapeptide injection in Experiment 2. A higher dose of devazepide (1200 microg/kg) also failed to inhibit preference conditioning by I.D. Polycose in Experiment 3. These results indicate that, although CCK(A) mechanisms play a role in the satiating effect of I.D. carbohydrates, they do not mediate their reinforcing effect. The present study, along with other recent reports, indicate that different mechanisms mediate the satiating and reinforcing actions of nutrients.

Animals↗

PubMed1991

Studies of three non-peptide cholecystokinin antagonists (devazepide, lorglumide and loxiglumide) in human isolated alimentary muscle and guinea-pig ileum.

1. Three recently described non-peptide cholecystokinin (CCK) antagonists (devazepide, lorglumide, loxiglumide) have been studied for their antagonism of the contraction to cholecystokinin-octapeptide (CCK-OP) in human alimentary muscle and guinea-pig intestine. 2. Each antagonist caused a concentration-dependent inhibition of the contraction induced by CCK-OP, regardless of regional and species differences. 3. The potencies of each drug, estimated by use of an adaptation of the Cheng & Prusoff equation, were similar in the different regions of human alimentary tract (weighted mean apparent pKB, +/- s.e. mean: devazepide, 5.76 +/- 0.08, n = 20; lorglumide, 5.82 +/- 0.04, n = 25; loxiglumide, 5.87 +/- 0.07, n = 24). 4. In contrast, the potencies differed markedly in the guinea-pig ileum. Apparent pKB values obtained by the same method as with human tissues were, mean +/- s.e.mean: devazepide, 10.61 +/- 0.61; lorglumide, 7.43 +/- 0.20; loxiglumide, 6.67 +/- 0.12. pKB values obtained from classical competition experiments were: devazepide, 10.09 +/- 0.09; lorglumide 7.70 +/- 0.12; loxiglumide 6.08 +/- 0.22. 5. The CCK receptors in human gut muscle from different regions seem to be similar, but there appear to be species differences.

Animals↗

PubMed1991

The CCK-A receptor antagonist devazepide but not the CCK-B receptor antagonist L-365,260 reverses the effects of chronic clozapine and haloperidol on midbrain dopamine neurons.

In this study, we examined the effects of the cholecystokinin-A (CCK-A) antagonist devazepide (MK 329) and the CCK-B antagonist L-365,260 to reverse the decrease in the number of spontaneously active dopamine (DA) cells in the ventral tegmental area and substantia nigra pars compacta after chronic haloperidol (HAL) or clozapine (CLOZ) treatment. The intravenous administration of devazepide (2 micrograms/kg) but not L-365,260 (2 micrograms/kg) reversed the reduction in the number of spontaneously active A9 and A10 DA cells produced by chronic HAL. Furthermore, devazepide also reversed the decrease in the number of spontaneously active A10 DA cells produced by chronic CLOZ administration. Overall, these results suggest that CCK-A but not CCK-B receptors play an important role in mediating or maintaining the chronic antipsychotic drug-induced effect on midbrain DA cells.

Animals↗

PubMed1994

Age-dependent effects of CCK and devazepide in male and female rats.

Peripheral administration of the brain/gut peptide cholecystokinin (CCK) has been demonstrated to inhibit food intake in a variety of species, and administration of the specific type A CCK receptor antagonist devazepide increases food intake in a variety of experimental paradigms. The potency of CCK to inhibit intake depends upon a variety of factors, but CCK is generally less potent under conditions of elevated food intake. At different developmental stages, rats' intake requirements differ as growth rates change. To determine whether CCK plays a variable role in the control of intake in rats of different ages, we examined the feeding-inhibitory effect of various doses of CCK and the feeding-enhancing potential of various doses of devazepide on glucose consumption (0.5 kcal/ml) in male and female rats at 45-70 and 110-130 days of age. CCK was more potent in older male and female rats than in younger rats, and inhibited intake in a dose-related fashion. In younger rats, the efficacy of CCK was attenuated and the inhibition was not dose related. Administration of devazepide had no effect on intake in younger rats of either sex, but significantly increased glucose consumption in the older rats. These data suggest that during a period of rapid growth and high levels of food intake relative to body weight, adolescent rats are relatively insensitive to exogenous CCK and endogenous CCK does not appear to play a significant role in controlling their intake.

Age Factors↗

PubMed1996

Devazepide increases food intake in male but not female Zucker 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.

Animals↗