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PubMed1994

Endogenous cholecystokinin is not a major regulator of food intake in the chicken.

This study investigated whether or not endogenous cholecystokinin exerts satiety effects in chickens. After several doses (0, 1, 2 and 4 micrograms.kg body weight-1) of intravenous injection of caerulein, the bile flow was increased in a dose-dependent fashion. However, the pharmacological level of caerulein failed to suppress the food intake of chickens. Two potent stimulators of endogenous cholecystokinin, i.e., soybean trypsin inhibitor and phenylalanine were administered to chickens before feeding and food intake was determined over 2 h. The soybean trypsin inhibitor and phenylalanine did not alter food intake. Devazepide, a cholecystokinin-A receptor antagonist, significantly decreased amylase release from the dispersed chicken pancreatic acini stimulated by caerulein. However, devazepide did not improve food intake of the chicken. The results obtained suggest that endogenous cholecystokinin may not act as a satiety signal in chickens.

Animals↗
PubMed1993

Characterization of a new diphenylpyrazolidinone cholecystokinin antagonist in vitro isolated rat pancreatic acini.

The effects of a newly developed diphenylpyrazolidinone cholecystokinin (CCK) antagonist LY219,057 were examined in the isolated rat pancreatic acini and compared with those of devazepide (previously designated L364,718 or MK-329). LY219,057 caused a concentration-dependent inhibition of 100 pM CCK octapeptide (CCK-8)-stimulated amylase release, with a half-maximal inhibition (ID50) at 287.5 +/- 28.4 nM and was 200 times less potent than devazepide (ID50 = 1.4 +/- 0.2 nM). The antagonism was competitive in nature because LY219,057 caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase secretion without altering the maximal increase. LY219,057 significantly inhibited amylase release in response to CCK-8 and cerulein but had no effect on amylase release stimulated by other receptor secretagogs or agent bypassing receptors. LY219,057, whether added at the beginning or 20 min after the CCK-8 stimulation, inhibited amylase release. This compound caused a residual inhibition of the action of CCK-8. Acini preincubated with 1.0 microM LY219,057 for 30 min at 37 degrees C were threefold less sensitive to CCK-8 than the acini preincubated without LY219,057. These results indicate that LY219,057 acts as a potent, competitive, and specific CCK receptor antagonist of the action of CCK on the exocrine pancreas.

Amylases↗
PubMed1998

Effects of epidermal growth factor on neonatal pancreatic growth in the guinea pig.

CONCLUSION: EGF and/or transforming growth factor-alpha (TGF-alpha) are likely to be important in the rapid pancreatic growth that occurs in the neonatal guinea pig. BACKGROUND: Rapid pancreatic growth is observed during the neonatal period in the guinea pig. The growth factors that are involved are not known but may include members of the EGF family. METHODS: Mini-osmotic pumps were implanted on the day of birth for continuous infusion of EGF (30 microgram/d). Pancreatic DNA, RNA, and protein contents were determined at 4 and 15 d, along with wet weights of the pancreas, duodenum, jejunoileum, colon, and gallbladder. Pancreatic EGF and TGF-alpha concentrations were measured in adult controls, in control neonates at 1, 4, 8, and 15 d, and also at 4 and 15 in guinea pigs receiving either EGF or the cholecystokinin receptor antagonist devazepide (25 nmol/kg/h). RESULTS: EGF infusion significantly increased the weight of the stomach and duodenum at 4 d and all the gastrointestinal organs, including the pancreas, at 15 d. Exogenous EGF increased pancreatic DNA, RNA, and protein content at 4 and 15 d. Endogenous EGF and TGF-alpha concentrations in the pancreas were significantly higher at birth than in adults (P < 0.001) and P < 0.01, respectively) and declined during the first 2 wk postpartum. At 15 d, EGF concentrations remained significantly higher than adult levels (P < 0.01), but TGF-alpha concentrations had declined to adult values. Infusion of EGF decreased concentrations of endogenous EGF in the pancreas at 4 and 15 d (both P < 0.05) and decreased TGF-alpha concentrations at 4 d (P < 0.001). Devazepide infusion caused a significant decrease in endogenous pancreatic EGF concentrations at 15 d (P < 0.05).

Aging↗
PubMed1991

'Anxiolytic' effect of CCK-antagonists on plus-maze behavior in mice.

The effects of systemic treatment with the CCK-B receptor antagonist L-365,260, its 3S-(-) enantiomer and the CCK-A receptor antagonist devazepide were assessed in the plus-maze procedure in mice. L-365,260 (1-1000 micrograms.kg-1 i.p.) produced a dose-dependent increase in the percentage of entries into, and the percentage of time spent in the open arms. Total arm entry was not consistently modified. Neither the 3S-(-) enantiomer of L-365,260 nor devazepide (both administered at 100-10,000 micrograms.kg-1) enhanced the exploratory behavior of mice. These results suggest that CCK-B, rather than CCK-A antagonists may possess 'anxiolytic' properties in mice.

Animals↗
PubMed1992

Morphine place conditioning is differentially affected by CCKA and CCKB receptor antagonists.

In the present study we have examined the interaction between the selective cholecystokinin (CCK)A and CCKB receptor antagonists, devazepide and L365-260 on morphine conditioned place preference (CPP). Using an unbiased procedure, morphine (1.5 mg/kg) produced a reliable CPP which was observed irrespective of the conditioning compartment type. Pretreatment with devazepide (0.001-0.01 mg/kg s.c.) produced a dose related attenuation of this response. At higher doses (0.1-1 mg/kg) this antagonism became variable and dependent on the training compartment with blockade only observed when conditioning was to the white/rough textured environment. This profile has also been reported for the serotonin (5-HT)3 receptor antagonist ondansetron. The CCKB antagonist L365-260 (0.000001-0.01 mg/kg) failed to antagonize the morphine CPP, if anything a mild potentiation was observed. To study this further we examined the interaction between L365-260 (0.01 mg/kg) and a subthreshold dose of morphine (0.3 mg/kg). At these doses neither drug elicited CPP, however when co-administered a significant CPP was recorded. Finally, L365-260 at 1 mg/kg induced a mild but significant CPP when administered alone. These results suggest a differential role of CCK receptor subtypes on reward-related behaviour and complement previous studies suggesting bimodal effects of CCK systems on mesolimbic dopamine function.

Animals↗
PubMed1993

Increased release of immunoreactive cholecystokinin octapeptide by morphine and potentiation of mu-opioid analgesia by CCKB receptor antagonist L-365,260 in rat spinal cord.

This is the first report showing, in an in vivo study, that systemic morphine produced a marked (89%, P < 0.01) increase of the cholecystokinin octapeptide (CCK-8) immunoreactivity in the perfusate of the rat spinal cord, an effect completely reversed by naloxone. Since CCK-8 has been shown to possess potent anti-opioid activity at a spinal level, a blockade of the spinal cholecystokinin effect would be expected to potentiate opiate analgesia. With tail flick latency as a nociceptive index, it was found that intrathecal (i.t.) injection of a novel CCKB antagonist L-365,260 produced a marked potentiation of the analgesic effect induced by the mu-opioid agonists morphine (4 mg/kg s.c.) or ohmefentanyl (32 ng i.t.). Similar effects were obtained with the CCKA antagonist devazepide at a dose 40-50 times higher than that of L-365,260. Both devazepide and L-365,260 showed a bell-shaped dose-response curve. The results confirm the notion that an increased release of CCK-8 may constitute a self-limiting process for opioid effects at the spinal level, and that it is the CCKB receptor which mediates the anti-opioid effect of CCK-8 in the rat spinal cord.

Analgesia↗
PubMed1996

Camostate- and caerulein-induced delay of gastric emptying in the rat: effect of CCK receptor antagonists.

The effect of camostate, a potent releaser of endogenous cholecystokinin (CCK), and of caerulein, an amphibian peptide mimicking the biological actions of CCK, as well as of selective CCK receptor antagonists on gastric emptying of liquids was studied in the rat. Oral administration of camostate (200 mg/kg with the liquid test meal preceded by the same dose 10 min before the meal) significantly delayed gastric emptying of saline, an effect which was completely blocked by previous administration of the CCKA receptor antagonist, devazepide, at a dose (1 mg/kg i.v.) unable to modify the emptying rate when administered alone. Caerulein (0.03-30 nmol/kg i.v.) also delayed the emptying rate in a dose-dependent manner, with an ID50 of 3.94 nmol/kg. The effect of the peptide was also inhibited by devazepide. The CCKB receptor antagonist, L365,260 (3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-yl)-N'-(3-methylphenyl)-urea; 3 mg/kg i.v.), was completely unable to modify the CCK (both endogenous and exogenous)-induced delay in gastric emptying. Repeated (7 days) camostate administration did not modify the gastric motor response to endogenous CCK, thus, suggesting that adaptation did not take place. These results demonstrate that endogenous and exogenous CCK delays gastric emptying of liquids through stimulation of CCKA receptors and suggest that adaptation of the gastric motor response to CCK does not occur.

Analysis of Variance↗
PubMed1994

Evidence for potentiation by CCK antagonists of the effect of cholecystokinin octapeptide in the elevated plus-maze.

Systemic treatment with cholecystokinin octapeptide (CCK-8, 2.5-10 micrograms/kg, s.c.), a non-selective CCK agonist, decreased the exploratory activity of mice in an elevated plus-maze. At higher doses (5-10 micrograms/kg) CCK-8 reduced the frequency of rearing, but only 10 micrograms/kg of CCK-8 significantly inhibited the number of line crossings in the open-field test. A preferential CCKB antagonist L-365,260 (1 and 100 micrograms/kg, i.p.) and a non-selective CCK antagonist proglumide (0.1-1 microgram/kg, i.p.) potentiated the anti-exploratory effect of CCK-8 (2.5 micrograms/kg). Devazepide, a preferential CCKA antagonist, only at a high dose (100 micrograms/kg) tended to increase the action of CCK-8 in the plus-maze. However, the concomitant treatment of CCK-8 with L-365,260 and proglumide, differently from devazepide, also suppressed the locomotor activity in the open-field test. Therefore, it is likely that the potentiation by CCK antagonists of the anti-exploratory effect of CCK-8 is related to the suppression of motor activity. This peculiar interaction between CCK-8 and CCK antagonists could be explained in the light of the opposite role of CCKA and CCKB receptors in the regulation of motor activity in mice.

Animals↗
PubMed1993

The effects of CCKA and CCKB antagonists on activity in the black/white exploration model of anxiety in mice.

In view of evidence suggesting that cholecystokinin (CCK) may have a role in the mediation of human panic disorders, it was predicted that CCK receptor antagonists may have anxiolytic-like activity in an animal model of anxiety, the black/white exploration test. Data revealed that, in mice, the CCKA receptor antagonist, devazepide (formerly L-364,718, MK-329), produced a clear anxiolytic-like profile with an inverted U-shaped dose-response curve centered around 5 micrograms/kg. Similarly, L-365,031, a specific, but less potent, CCKA antagonist, also produced a profile consistent with weak anxiolysis but only at 5 micrograms/kg. By direct contrast, the potent and specific CCKB antagonist L-365,260 had no robust anxiolytic-like effects in this test. Therefore, these data suggest that devazepide has the greatest effects in this model, that L-365,031 is only marginally active, and that L-365,260 is without influence. These results suggest that CCKA receptor mechanisms are involved in the mediation of anxiolytic-like effects in the black/white model of exploration in mice.

Animals↗
PubMed1996

Intracerebroventricular injection of CCK reduces operant sugar intake in pigs.

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.

Animals↗
PubMed1992

Failure of cholecystokinin antagonists to modify the discriminative stimulus effects of cocaine.

Enhancement of brain dopamine (DA) activity is believed to be an important mechanism underlying the discriminative stimulus effects of cocaine in animals and the subjective effects of cocaine in people. Cholecystokinin (CCK) receptors, which are colocalized with DA receptors in several brain regions, have been implicated as modulators of DA activity, leading to speculation that CCK-based drugs might be developed as therapeutics for cocaine abuse. In the present study, the effects of cocaine alone and after pretreatment with the selective CCKA antagonist devazepide and the selective CCKB antagonist CI 988 were determined in squirrel monkeys trained to discriminate cocaine (1.0 mg/kg) from saline. When tested alone, cocaine engendered dose-related increases in the percentage of cocaine-appropriate responses, reaching virtually exclusive responding on the cocaine-associated lever after doses of 1.0 mg/kg or greater. Pretreatment with a wide range of doses of either devazepide (0.01-3.0 mg/kg) or CI 988 (0.3-30 mg/kg) did not systematically alter the discriminative stimulus effects of any dose of cocaine. The results do not support a role for CCK antagonists in the pharmacotherapy of cocaine abuse.

Animals↗
PubMed1994

Evidence for the contribution of CCKB receptor mechanisms to individual differences in amphetamine-induced locomotion.

Recent evidence shows that rats exhibit individual differences in their locomotor response to amphetamine (AMP). Moreover, evidence has accumulated showing that high-AMP responders exhibit more mesolimbic dopaminergic (DAergic) activation in response to AMP treatment than low-AMP responders. Cholecystokinin (CCK) is a peptide that is colocalised with mesolimbic DA and exerts complex modulatory actions on DA function. Two CCK receptor subtypes have been identified and selective antagonists have been developed. To examine the possible contribution of endogenous CCK mechanisms to individual differences in responsivity to AMP treatment, male Wistar rats were divided into low- and high-AMP responders based on a median split of their locomotor response to AMP and the effects of the selective CCK antagonists L365-260 (CCKB; 0.01, 0.1, 0.5 mg/kg; n = 16) and devazepide (CCKA; 0.001, 0.01, 0.1 mg/kg; n = 23) were determined. Results showed that L365-260 (0.1 mg/kg) potentiated AMP-induced hyperactivity in low-AMP responders but did not affect AMP-induced hyperactivity in high-AMP responders. Devazepide was without effect in both groups of animals. This pattern of results suggests that CCKB, but not CCKA, receptor mechanisms contribute to interindividual variation in responsivity to AMP.

Amphetamine↗
PubMed1994

Receptor mediation of the stimulus properties of cholecystokinin.

Recently, Melton, Kopman, and Riley (20) reported the rapid acquisition of drug discrimination learning using the sulfated form of cholecystokinin (CCK) within the conditioned taste aversion baseline of drug discrimination learning. The present study was designed to explore the receptor mediation of the stimulus properties of CCK within this procedure. Every fourth day, experimental subjects were given CCK-saccharin-LiCl pairings, and on the intervening recovery days, saccharin alone. Once discriminative control was established, doses of the CCK receptor antagonists devazepide (CCK-type A receptor subtype) and L-365,260 (CCK-type B receptor subtype) were administered in combination with the training dose of CCK. Unlike L-365,260 (1-1000 micrograms/kg), devazepide (1 microgram/kg) blocked the CCK stimulus, suggesting that within this design CCK's stimulus properties are mediated by the CCK-type A receptor subtype.

Animals↗
PubMedDate not supplied

Electrophysiological and autoradiographical evidence for cholecystokinin A receptors on rat isolated nodose ganglia.

The sulphated octapeptide, cholecystokinin (CCK-8S), is believed to be a neurotransmitter of vagal sensory neurones, and here the presence of functional receptors for CCK-8S in the rat vagus nerve has been investigated by electrophysiological and autoradiographic techniques. CCK-8S caused concentration-dependent depolarizations when superfused over the rat isolated nodose ganglion at 37 degrees C as measured by a silicone grease gap technique. Concentration-response curves to CCK-8S were shifted to the right by low concentrations of the CCKA receptor antagonist, Devazepide, but not by the CCKB receptor antagonist, L-365,260, data which indicate that receptors were of the CCKA subtype. Consistent with this notion, the CCKB agonist, unsulphated CCK-8, was without effect until high concentrations (> 1 microM) were used. A synthetic analogue of CCK-8S, D-Tyr25(Nle28,31)-CCK 25-33S, which has been reported to be more stable and peptidase-resistant than CCK-8S, was equipotent with CCK-8S in depolarizing the nodose ganglion. When D-Tyr25(Nle28,31)-CCK 25-33S was labelled with 125I, it bound to tissue sections of nodose ganglion. By light microscopic autoradiography, silver grains were found to be highly localized over cell bodies of vagal sensory neurones. An excess of CCK-8S inhibited binding as did Devazepide, but not L-365,260, confirming that binding sites were CCKA subtype receptors. These results indicate the existence of functional CCKA receptors in the nodose ganglion and strengthen the case for the involvement of vagal sensory neurones in gastric emptying and satiety.

Animals↗
PubMed1994

Distribution of cholecystokinin receptors in the bovine brain: a quantitative autoradiographic study.

Quantitative in vitro receptor autoradiography was used to study the distribution of cholecystokin receptors in the bovine brain. [125I]Bolton-Hunter cholecystokinin octapeptide binding was described in whole hemisphere sagittal and coronal sections using cholecystokinin octapeptide, devazepide and L-365,260 as competitors to identify the subtypes. High levels of cholecystokinin receptors were found in the cortex, where they presented a laminar distribution which varied from area to area. The basal ganglia, the caudate nucleus, nucleus accumbens and putamen presented high to moderate levels of cholecystokinin binding, whereas only very low labelling was found in the globus pallidus. Cholecystokinin binding was present in all portions of the bovine hippocampus; high levels were found in the dentate gyrus, CA1 subfield of Ammon's horn, subiculum and presubiculum. Moderate to high levels were also found in the amygdala, inferior colliculus and olfactory tract, while most of the hypothalamic and thalamic nuclei exhibited very low or no cholecystokinin binding. Low cholecystokinin binding was uniformly distributed across cell layers of the bovine cerebellar cortex. Competition of [125I]Bolton-Hunter cholecystokinin octapeptide binding in the cortex, nucleus accumbens, caudate nucleus, hippocampus, cerebellum and brainstem was much greater in the presence of L-365,260 than devazepide, thereby suggesting that the majority of cholecystokinin receptors in these regions are of the cholecystokinin-B subtype. The results of this study, when compared to distribution profiles in other mammalian species, provide further evidence for species differences in the distribution of cholecystokinin receptors in the brain. The results also support the possible interaction between cholecystokinin and dopaminergic systems in areas of the brain containing dopaminergic terminals, such as the frontal cortex, nucleus accumbens, caudate-putamen and olfactory tubercle.

Animals↗
PubMed1993

Anti-exploratory effect of N-methyl-D-aspartate in elevated plus-maze. Involvement of NMDA and CCK receptors.

N-Methyl-D-aspartate (NMDA, 20 mg/kg) produced a clear decrease in mouse exploration in open parts of an elevated plus-maze. Paradoxically, 40 mg/kg NMDA did not modify the behavior of the mice in the plus-maze. NMDA at a dose of 80 mg/kg again depressed the exploratory activity of mice, but this effect was accompanied with tremor and compulsive tail biting. The 'anti-exploratory' dose of NMDA (20 mg/kg) increased, whereas the 'tremorigenic' dose (80 mg/kg) significantly decreased the number of cholecystokinin (CCK) binding sites in the mouse cerebral cortex. The competitive NMDA antagonist (+/-)-CPP (2.5-5 mg/kg) and the non-competitive antagonist MK-801 (0.25 mg/kg) antagonized the anti-exploratory effect of NMDA (20 mg/kg). The tricyclic antidepressant imipramine (5 mg/kg, but not 1 or 10 mg/kg) also attenuated the inhibition of exploratory activity induced by NMDA. Of three CCK receptor antagonists tested, the unselective CCK antagonist proglumide (1 mg/kg, but not 0.1 and 10 mg/kg) significantly opposed the anti-exploratory action of NMDA. The selective CCK antagonists L-365,260 (1 microgram/kg) and devazepide (1 microgram/kg) were evidently weaker antagonists of NMDA. Furthermore, 10 micrograms/kg of L-365,260, a CCK-B receptor antagonist, and 1 mg/kg of devazepide, a CCK-A receptor antagonist, even tended to augment the effect of NMDA in the plus-maze. The results of the present study seem to give some support to the notion that not only NMDA receptors, but also CCK-ergic mechanisms are involved in the modulation of anti-exploratory action of NMDA in the elevated plus-maze.

Analysis of Variance↗
PubMed1997

The effect of centrally administered CCK-receptor antagonists on food intake in rats.

Cholecystokinin (CCK) receptors are classified as two subtypes, designated CCK(A) and CCK(B), and both subtypes are found in brain and peripheral tissues of rats. CCK-8 has been shown to act peripherally to reduce meal size, and this satiating action can be blocked by CCK(A)-receptor antagonists. Recent evidence suggests that, in addition to the peripheral action of CCK, central CCK mechanisms may also be involved in satiety. Central administration of proglumide, a mixed CCK-receptor antagonist (CCK(A) > CCK(B)) has been shown to increase food intake and block the satiating effect of peripherally administered CCK-8 (15). In an attempt to replicate and extend these results, rats were given injections of proglumide or selective CCK-receptor antagonists into the lateral ventricle prior to a peripheral injection of CCK-8 or saline. Only proglumide stimulated an increase in 30-min test meal intake and attenuated the satiating effect of CCK-8. Two selective CCK(A)-receptor antagonists, lorglumide and devazepide, did not increase intake significantly when given alone, and they did not attenuate the effect of peripherally administered CCK-8. The selective CCK(B)-receptor antagonist, L365,260, reduced intake at all doses tested except the lowest. The lowest dose did not increase intake when given alone and did not attenuate the inhibitory effect of CCK on test-meal intake. Finally, a combination of devazepide and L365,260 did not increase intake or block the effect of peripherally administered CCK-8. These results suggest that CCK released by neurons in the brain and acting on central CCK(A)- and CCK(B)-receptors is not necessary for the control of meal size or for the satiating effect of peripherally administered CCK-8 in rats under our experimental conditions.

Animals↗
PubMed1996

Cholecystokinin A receptor antagonist inhibits feed memory in Japanese quail.

Cholecystokinin (CCK) modulates learning and memory processes in mammals. The main objective of this work was to study the effect of two cholecystokinin receptor antagonists (CCKA antagonist devazepide and CCKB antagonist PD135158) on feed memory processes in Japanese quail. Memorization of colored food was measured by comparing the feeding behavior of 6- to 8-day-old quails during two successive sessions of 10 min after a 30-min fast in the test box, intersession interval: 24 h. The CCKA antagonist devazepide (0.1 mg/kg, b.wt) injected after the first session appears to disrupt feed memory formation. The CCKB antagonist PD135158 at the same dose induced a similar trend, but no significant effect on feed memorization could be measured. It is suggested that CCKA antagonist inhibits feed memory processes.

Animals↗