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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↗
PubMed1992

Devazepide antagonizes the inhibitory effect of cholecystokinin on intake in sham-feeding rats.

3S(-)-N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl) -1H-indole-2-carboxamide (devazepide), a potent and selective cholecystokininA (CCKA) antagonist, has been shown to reverse the inhibitory effect of exogenously administered CCK-8 on food intake. In all tests, however, the inhibition of food intake could have been due not only to the CCK-8 administered but also to synergistic interactions between administered CCK-8 and endogenous satiety signals, such as glucagon or CCK released from the small intestine, elicited by the postingestive effects of the test diet. To eliminate these possible interactions, we investigated the effect of devazepide on the inhibitory effect of CCK-8 on the intake of a milk diet during 30 min of sham feeding, a procedure that minimizes or eliminates the postingestive satiating effect of food. Under these conditions, devazepide was a potent antagonist of the inhibitory effect of CCK-8 (16 mumol/kg, IP): The approximate ED50 was 625 ng/kg (1.3 nmol/kg) and the threshold dose was between 62.5 and 625 ng/kg.

Animals↗
PubMed1994

Cholecystokinin- and dexfenfluramine-induced anorexia compared using devazepide and c-fos expression in the rat brain.

It has been proposed that there might be a link between the anorectic actions of cholecystokinin (CCK) and serotonin (5HT). The present study compared the patterns of c-fos protein-like immunoreactivity (FLI) induced in rat brain by CCK and the indirect 5HT agonist dexfenfluramine (DFEN), as well as the ability for devazepide, a CCK-A receptor antagonist, to antagonize both anorexia and FLI induced by these agents. Devazepide reversed the anorectic effect of CCK but not that of DFEN in food deprived rats. The FLI induced by CCK and DFEN occurred in similar brain regions, but in different subdivisions. Such regions included the bed nucleus of the stria terminalis (BST), the lateral central nucleus of the amygdala (CeL), and the lateral parabrachial nucleus (LPB). Devazepide abolished the FLI induced by CCK in most of these brain regions, but had no effect on FLI induced by DFEN. These results suggest that the LPB-CeL/BST pathway might be responsible for the anorectic effects of both CCK and DFEN, but different parts or neuronal populations in these structures might be differentially engaged by CCK and DFEN. The putative interaction between CCK and 5HT might happen along this pathway, rather than in the periphery.

Animals↗
PubMed1994

The CCKA receptor antagonist devazepide inhibits the effect of apomorphine on vasopressin release in pigs.

1. A transient increase in plasma vasopressin concentrations represents a physiological correlate of nausea in animals that vomit. 2. The CCKA receptor antagonist devazepide has previously been shown to inhibit vasopressin release induced in pigs by intravenous (i.v.) CCK. 3. This study investigated whether devazepide (70 micrograms/kg i.v.) would affect vasopressin secretion induced in pigs (n = 6) by the emetic drug apomorphine (25 micrograms/kg i.v.). 4. Apomorphine stimulated vasopressin release in the 30 min period following injection; this effect was prevented by prior administration of devazepide. 5. The results suggest that CCKA receptor antagonists may have the ability to prevent nausea and/or emesis.

Animals↗
PubMed1997

Mutational analysis of the putative devazepide binding site of the CCK(A) receptor.

Recently a molecular model was proposed for the binding site of the antagonist 3S(-)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl) -1H-indole-2-carboxamide (devazepide) on the cholecystokinin-A (CCK(A)) receptor (Van der Bent et al., 1994. Drug Design Discov. 12, 129-148). Fifteen amino acids were identified, including hydrophilic ones such as Ser139, Asn349 and Ser379, that might interact with the carboxamide moiety in devazepide. To provide mutational evidence for this model, wild-type and mutant receptors (S139A, N349A and S379A) were transiently expressed and compared with respect to the ability of devazepide to inhibit binding of radiolabelled cholecystokinin-(26-33)-peptide amide (CCK-8) and CCK-8-evoked Ca2+ mobilization. The data presented suggest the involvement of the three residues in antagonist binding, although to a different extent. However, it does not seem likely that hydrogen bonds are the driving force in view of the relatively minor changes in receptor affinity and activity.

Animals↗
PubMed1997

Devazepide attenuates dl-fenfluramine-induced suppression of gastric emptying but not food intake in the 17 h food-deprived rat.

Recently a number of studies have provided evidence which suggests that CCK and 5-HT interact in the control of food intake. The present experiments further examine this mechanism and the possibility that CCK and 5-HT interact in the control of gastric emptying. The selective CCK-A receptor antagonist, devazepide, (0.03-3.0 mg/kg) administered alone had no intrinsic effect on gastric emptying. Devazepide (0.1 and 0.3 mg/kg) blocked dl-fenfluramine-induced (3.0 mg/kg) suppression of gastric emptying. However, devazepide (0.03-3.0 mg/kg) failed to attenuate the anorectic effect of the same dose of dl-fenfluramine. These results suggest that under the present experimental conditions CCK and 5-HT interact in the regulation of gastric emptying but not food intake. Thus the interaction between CCK and 5-HT in the regulation of gastric emptying appears not to affect the control of ingestive behaviour.

Animals↗
PubMed1996

Impairment of stress adaptive behaviours in rats by the CCKA receptor antagonist, devazepide.

1. Cholecystokinin (CCK) is released during stress both in limbic and hypothalamic areas suggesting that CCK could participate in modulating neuroendocrine as well as behavioural responses to stress. 2. In this study we have examined the effect of CCK receptor antagonists on the retention of the immobility response to a forced-swim stress in rats. In this test, rats are forced to swim during 15 min (conditioning period) and 24 h later, the duration of immobility is measured during a period of 5 min (re-test period). During the conditioning period rats display a period of vigorous activity, followed by progressive inactivity. During the re-test period rats remain 70-80% of the time in an immobile posture. 3. The CCKA receptor antagonist, devazepide (MK-329) but not the CCKB receptor antagonist, L-365,260, administered s.c. immediately before the conditioning period, decreased the duration of acquired immobility during the re-test period. The effect of devazepide was prevented by cholecystokinin octapeptide (CCK-8; 40 micrograms kg-1, s.c) as well as by the selective glucocorticosteroid GII receptor agonist, dexamethasone (30 micrograms kg-1, s.c.) 4. Neither corticosterone nor ACTH plasma levels measured both after the re-test period and after the conditioning period were modified by devazepide treatment. 5. The results suggest a role for CCK in the behavioural adaptation to stress and indicate a relationship between CCK systems and glucocorticoids in the neuronal mechanisms involved in the acquisition of adaptive behaviours to stress.

Adaptation, Physiological↗
PubMed1992

Pancreatic atrophy in rats produced by the cholecystokinin-A receptor antagonist devazepide.

According to recent reports, the powerful and selective cholecystokinin (CCK)-A receptor antagonist devazepide (also referred to as L-364,718 or MK-329) is without effect on the weight of the pancreas. This has been interpreted to mean that basal and meal-stimulated endogenous CCK does not play a major role in the normal maintenance of the pancreas. In the present study we show that continuous subcutaneous infusion of devazepide effectively and dose-dependently reduced the weight of the pancreas both in normal rats and in hyperCCKemic rats (because of pancreaticobiliary diversion). The maximum reduction of the pancreatic weight was 40%. Maximum or near-maximum effects were seen with a dose of 200 micrograms/kg/h. The DNA content of the pancreas was also reduced. The reduction in weight and DNA content of the pancreas was maximal after 10 days. Provided that devazepide acts solely by inhibiting CCK-A receptors, we can conclude that endogenous CCK plays an important role in both normal and stimulated growth of the rat pancreas.

Animals↗
PubMed1990

SCH 23390-induced hypophagia is blocked by the selective CCK-A receptor antagonist devazepide, but not by the CCK-B/gastrin receptor antagonist L-365,260.

The selective dopamine D-1 receptor antagonist SCH 23390 (30 micrograms/kg, SC) significantly reduced palatable food consumption by nondeprived rats in a 30-min test period. Prior administration of the selective CCK-A receptor antagonist devazepide (MK 329; L-364,718) blocked the hypophagic effect of SCH 23390. In contrast, prior administration of the selective CCK-B/gastrin receptor antagonist L-365,260 had no effect. Devazepide did not antagonize a matched hypophagic effect produced by the dopamine D-2 receptor antagonist raclopride (0.1 mg/kg, SC). These data direct attention to possible dopamine-cholecystokinin interactions in relation to the control of ingestional responses, and, more specifically, indicate possible functional relationships between D-1 and CCK-A receptor mechanisms.

Animals↗
PubMed1996

Lack of interaction between devazepide and 8-OH-DPAT-induced hyperphagia in the rat.

Recently, a number of studies have provided evidence suggesting that CCK and 5-HT interact in the control of food intake. However, the majority of these studies have relied on the administration of exogenous CCK to investigate potential interactions. The aim of the present study was to focus on the potential role of endogenous CCK in 5-HT-CCK interactions. Our prediction was that the CCKA antagonist, devazepide, alone would potentiate the hyperphagic effect of the 5-HT1A agonist, 8-OH-DPAT, in free-feeding rats. The results showed that devazepide, at a dose that had no intrinsic effect (1.0 mg/kg), did not enhance the hyperphagic effect of 8-OH-DPAT (100 and 300 micrograms/kg). This suggests that when serotonergic inhibitory activity is reduced by 5-HT1A-receptor stimulation, there is no compensatory increase of endogenous CCK activity to excite 5-HT neurons and thereby inhibit food intake.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Combined dose-ratio analysis of cholecystokinin receptor antagonists, devazepide, lorglumide and loxiglumide in the guinea-pig gall bladder.

1. Interactions between cholecystokinin octapeptide (CCK-8) and CCKA-receptor antagonists derived from benzodiazepines (devazepide) and glutamic acid (lorglumide and loxiglumide) have been examined in an improved bioassay using the guinea-pig, isolated, gall bladder preparation. 2. The presence of CCKB-receptors in the assay was provisionally-ruled out on the basis of the low potency of pentagastrin in the assay. By applying analyses of both agonism and antagonism, pentagastrin was shown to behave as a partial agonist at the CCKA-receptor. 3. Devazepide, lorglumide and loxiglumide behaved as simple competitive antagonists of CCKA-receptors and pKB values of 9.98, 7.59 and 7.07 were estimated, respectively. 4. Application of a combined dose-ratio analysis to the interactions between CCK-8 and combinations of devazepide/lorglumide and devazepide/loxiglumide indicated that these molecules behave as syntopic, competitive, antagonists at the CCKA-receptor. 5. We conclude that the guinea-pig gall bladder assay contains a homogeneous population of CCKA-receptors and offer an explanation for the differences between our results and those obtained recently by Maubach et al. (1991) which were taken as preliminary evidence for CCKA-receptor heterogeneity.

Analysis of Variance↗
PubMed1999

Duodenal loading with glucose induces fos expression in rat brain: selective blockade by devazepide.

The role of CCK in mediating neuronal activity in the brain in response to dietary carbohydrate was measured by detecting Fos immunoreactivity in response to duodenal glucose load in rats after administration of the CCK-A receptor antagonist devazepide. In adult, male Sprague-Dawley rats, infusion for 30 min of 545 mg (2.18 kcal) dextrose through a duodenal cannula induced Fos expression in the nucleus of the solitary tract (NTS), area postrema (AP), lateral division of the central nucleus of the amygdala (CeAL), and the external subnucleus of the lateral parabrachial nucleus (LPBE). Devazepide treatment (1 mg/kg) attenuated Fos expression in the NTS and AP by 81 and 78%, respectively, but not in the CeAL or LPBE. These results indicate that central neuronal activation is elicited by dietary glucose in the intestinal lumen and that activation of neurons in the NTS and AP is mediated by CCK-A receptors.

Animals↗
PubMed1995

Devazepide reverses the anorexic effect of simmondsin in the rat.

Simmondsin, a glycoside extracted from jojoba meal (Simmondsia chinensis), causes a reduction in food intake after oral administration. To investigate the mechanism by which simmondsin reduces food intake, fasted and free-feeding rats were given simmondsin-supplemented food and simultaneously injected with devazepide, a specific antagonist of peripheral-type cholecystokinin receptors (CCKA receptors). In free-feeding rats, supplementation of food with 0.5% simmondsin caused a reduction in food intake of +/- 40% in the period of 4 h following food presentation. Intraperitoneal injection of 100 micrograms devazepide/kg body weight prevented this effect. In rats fasted for 20 h, the food intake in the 30 min after presentation of food supplemented with 0.15% or 0.50% simmondsin was reduced in a dose-related manner; this was also inhibited by simultaneous application of devazepide. It is suggested that peripheral CCKA receptors are involved in the effect of simmondsin on food intake. However, a direct effect of simmondsin on CCKA receptors has been excluded, since simmondsin was unable to cause contraction of the guinea-pig gallbladder in vitro.

Acetonitriles↗
PubMed1993

[Effect of cholecystokinin and its antagonists lorglumide, devazepide, and L-365,260 on gastrointestinal motility in rats].

Cholecystokinin (CCK) plays an important role in gallbladder contraction and gut motility. Sincalide (CCK-8) evoked guinea pig isolated ileum contraction at 10(-5)-10(-1) mumol.L-1 in a concentration-dependent manner, EC50 being 207 pmol.L-1. It delayed the gastric emptying as well. The rate of inhibition of gastric emptying was 71 +/- 12% at 100 micrograms.kg-1 by ip. Sincalide antagonists: lorglumide, devazepide, and L-365,260 antagonized the ileal smooth muscle response to sincalide in a concentration-dependent manner. Their pA2 were 7.30, 10.02, and 7.77, respectively. Lorglumide, devazepide, and L-365,260 inhibited the delaying of gastric emptying evoked by sincalide. The IC50 were 0.11, 0.0064, and 0.66 mg.kg-1, respectively.

Animals↗
PubMed1996

The effects of cholecystokinin A and B receptor antagonists, devazepide and L 365260, on citalopram-induced decrease of exploratory behaviour in rat.

The present study has been divided into two sets. In the first set, the aim of the experiments was to investigate the dose-response effect of selective serotonin re-uptake inhibitor (SSRI) citalopram on rat exploratory behaviour in the elevated plus-maze. In the second set of experiments, the effect of cholecystokinin (CCK) CCKA and CCKB receptor antagonists, devazepide and L 365260, on citalopram-induced decrease of exploratory behaviour in the elevated plus-maze was studied. Citalopram (5 and 10 mg/kg) decreased the number of open and total arm entries, line crossings on open arms, and percentage of time spent exploring in open arm. Dose 15 mg/kg was without any effect on rat exploratory behaviour. Devazepide (0.01 and 1.0 mg/kg) failed to modify any of the citalopram-induced changes observed. L 365260 (1.0 mg/kg) reversed most of the effects of citalopram: the numbers of open and total arm entries, the number of line crossings, and the percentage of time spent exploring in open arms. L 365260 at dose level 0.01 mg/kg was ineffective. These results support the involvement of the CCKB receptor subtype in SSRI-induced anxiogenic-like effects in rodents.

Animals↗
PubMed1996

The action of the cholecystokinin-A receptor antagonist, devazepide, on the digestive system of the chicken.

The influence of the cholecystokinin (CCK)-A receptor antagonist, devazepide (DVZ), on the chicken digestive tract was investigated. The passage of food from the crops of birds treated with DVZ was not significantly different from that of the control. DVZ treatment did not inhibit the biliary flow stimulated by the CCK analogue, caerulein. Dispersed chicken pancreatic acini stimulated with CCK were treated with various concentrations of DVZ. At 10-5 M, DVZ completely inhibited amylase release; this concentration was much higher than those reported to have similar effects in mammals. The results suggest that the action DVZ as a CCK antagonist in the chicken is very weak.

Amylases↗
PubMed1991

Hypolocomotion induced by peripheral or central injection of CCK in the mouse is blocked by the CCKA receptor antagonist devazepide but not by the CCKB receptor antagonist L-365,260.

The pharmacological mechanisms underlying the hypolocomotion induced by intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) injections of cholecystokinin octapeptide sulphated (CCK) in the mouse were examined using selective CCKA and CCKB receptor antagonists. Locomotor activity was measured in photocell cages. CCK (10 micrograms/kg i.p.) significantly reduced activity in mice tested in the afternoon but not in the morning, indicating a circadian variation in the effect of the peptide. The hypolocomotion induced by i.p. injection of 10 micrograms/kg CCK and i.c.v. injection of 3.5 micrograms CCK was reversed by the selective CCKA antagonist devazepide, but not by the selective CCKB antagonist L-365,260. This suggests that CCK-induced hypolocomotion is mediated by CCKA receptors. Larger doses of CCK were required to induce hypolomotion when injected i.c.v. (3.5 micrograms per mouse) than when given i.p. (10 micrograms/kg i.e. 0.2 microgram per mouse). Furthermore the latency to onset of the hypolocomotion after i.c.v. injection of CCK was longer than after i.p. injection of CCK. These data suggest that the sedative action of i.c.v. CCK may be due to leakage of the peptide from the brain and subsequent activation of peripheral CCKA receptors. However a role for CCKA receptors in the CNS in mediating hypolocomotion induced by i.c.v. injection of CCK cannot be ruled out on the basis of the present data.

Animals↗