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PubMed2004

Exogeneous and endogenous CCK inhibit ethanol ingestion in Sardinian alcohol-preferring rats.

Ethanol ingestion, like food ingestion, stimulates release of the signaling molecule cholecystokinin (CCK) from the small intestine. Here, we investigated the possibility that ethanol-induced CCK release might be a negative-feedback control of ethanol ingestion, similar to its function as part of the mechanism by which ingested food produces meal-ending satiation. We used Sardinian alcohol-preferring (sP) and Marchesian Sardinian (msP) alcohol-preferring rats, two apparently identical substrains that spontaneously ingest pharmacologically relevant amounts of ethanol, as well as their background strain, Wistar (W) rats. We demonstrated that: (1) intraperitoneal (IP), but not intracerebroventricular, injections of 0.5-4 microg/kg CCK-8 produced transient, dose-related reductions in 10% ethanol ingestion; (2) this inhibitory effect of CCK-8 on ethanol intake appeared behaviorally similar to its inhibitory action on ingestion of sucrose solutions; (3) the inhibitory effect of IP CCK-8 on ethanol ingestion occurred without evidence of tolerance when tests were repeated on consecutive days; (4) IP CCK-8 reduced ethanol intake despite simultaneously reducing blood ethanol levels (BALs); and (5) antagonism of CCK1 receptors with devazepide increased ethanol intake, indicating that endogenous CCK normally limits the size of bouts of ethanol ingestion. These results implicate peripheral CCK in the control of ethanol ingestion in sP and msP alcohol-preferring rats.

Alcohol Drinking↗
PubMed2004

The ontogeny of the postingestive inhibitory effect of peptone in rats.

The ontogeny of the postingestive inhibitory control of intake by protein digestion products was investigated by administering gastric preloads of a peptone that was a hydrolysate of meat and that decreased intake in adult rats [Am. J. Physiol., Regul. Integr. Comp. Physiol. 276 (1999) R1623; Am. J. Physiol., Regul. Integr. Comp. Physiol. 277 (1999) R1144]. Gastric preloads of saline or peptone, or sham preloads were given 5 min before a 30-min, independent ingestion test in which pups had access to a sweet, high-fat milk diet. Preloads of isotonic peptone reduced intake significantly more than preloads of isotonic saline on postnatal day (P) 18, but not on P12. Pretreatment with the CCKA receptor antagonist devazepide (600 microg/kg ip) did not change the inhibitory effect of isotonic peptone. Thus, the inhibitory effect of peptone on P18 was apparently not mediated by endogenous CCK acting at CCKA receptors. In contrast to isotonic peptone, preloads of hypertonic peptone did not decrease intake more than preloads of hypertonic saline on P12, P18, or P24. We conclude that if the isotonic peptone used in these experiments is an adequate model of the digestion products of dietary protein at these postnatal ages, then the postingestive inhibitory control of intake by digestion products of dietary protein during independent ingestion appears between P13 and P18.

Age Factors↗
PubMed1997

CCK-8 activates hepatic vagal C-fiber afferents.

Intravenous administration of 2 micrograms/kg CCK-8 increased the single unit activity of 54% of hepatic vagal afferent fibers. Conduction velocity tests indicated that all of these units were C fibers. The increase in hepatic vagal activity produced by CCK-8 was significantly reduced by i.v. administration of 200 micrograms/kg of the CCKA receptor antagonist devazepide. Control comparisons indicated that this reduction was not an artifact of tachyphylaxis resulting from repeated administration of CCK-8. Further, the inability of pretreatment with atropine and hexamethonium to reduce the increases in hepatic vagal activity produced by CCK-8 suggests that the latter effect was not secondary to changes in gastrointestinal motor function. These outcomes demonstrate that activation of CCKA receptors by CCK-8 increases hepatic vagal afferent activity and support the view that the duodenal satiety action of CCK is mediated by the hepatic branch.

Animals↗
PubMed2002

Effects of evodiamine on gastrointestinal motility in male rats.

The effects of evodiamine on gastric emptying, gastrointestinal transit, and plasma levels of cholecystokinin (CCK) were studied in male rats. Evodiamine, isolated from the dry unripened fruit of Evodia rutaecarpa Bentham (a Chinese medicine named Wu-chu-yu), has been recommended for abdominal pain, acid regurgitation, nausea, diarrhea, and dysmenorrhea. Gastrointestinal motility was assessed in rats 15 min after intragastric instillation of a test meal containing charcoal and Na(2)51CrO(4). Gastric emptying was determined by measuring the amount of radiolabeled chromium contained in the small intestine as a percentage of the initial amount received. Gastrointestinal transit was evaluated by calculating the geometric center of distribution of the radiolabeled marker. Blood samples were collected for CCK radioimmunoassay (RIA). After administration of evodiamine (0.67-6.00 mg/kg), both gastric emptying and gastrointestinal transit were inhibited, whereas the plasma concentration of CCK was increased in a dose-dependent manner. The selective CCK(1) receptor antagonists, devazepide and lorglumide, effectively attenuated the evodiamine-induced inhibition of gastric emptying and gastrointestinal transit. L-365,260 (3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-N'-(3-methylphenyl)-urea), a selective CCK(2) receptor antagonist, did not alter the evodiamine-induced inhibition of gastric emptying and gastrointestinal transit. These results suggest that evodiamine inhibits both gastric emptying and gastrointestinal transit in male rats via a mechanism involving CCK release and CCK(1) receptor activation.

Animals↗
PubMed1996

Antidepressant-like effects of CCK(B) receptor antagonists: involvement of the opioid system.

RB 101 (N-[(R,S)-2-benzyl-3-[(S)-2-amino-4-methylthiobutyldithio]-1-oxopr opyl]-L -phenylalaninebenzyl ester), a systemically active inhibitor of enkep halin catabolism, has been shown to elicit antidepressant-like effects in mice, both in the forced-swimming and in the conditioned suppression of the mobility tests. The same type of response has been also observed following administration of the cholecystokinin CCK(B) receptor antagonist L-365,260 ((3R)-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin -3-yl)-3 -methylphenylurea). In terestingly, the delta-opioid receptor antagonist naltrindole (17-cyclopropylmethyl-6,7-dehydro-4,5alpha-epoxy-3,14-dihydroxy-6, 7,2'-3'-indolomorphinan) blocks the effect of both RB 101 and L-365,260 in the conditioned suppression of the motility test. In this work we have investigated the involvement of the opioid system in the antidepressant response to the CCK(B) receptor antagonist L-365,260 in the forced-swimming test in mice. The effect of L-365,260 was decreased by the delta-opioid receptor antagonist naltrindole. Furthermore, the CCK(B) receptor agonist, BC 264 (Boc-Tyr(OSO3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2), blocked the antidepressant-like effect of RB 101 while CCK-8 (H-Asp-Tyr(OSO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2) enhanced the effect of this drug, probably through stimulation of central CCK(A) receptors, since the CCK(A) receptor antagonist devazepide ((3S)-(-)-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin++ +-3-yl)-1H-indole-2 -carboxamide) abolished the CCK-8-induced potentiation of the RB 101 effect. In addition, RB 101 enhanced the effect of L-365,260. Such an effect was blocked by the delta-opioid receptor antagonist naltrindole. These data further support the involvement of opioid receptors in the antidepressant-type effect induced by CCK(B) receptor blockers and support the hypothesis of a regulatory role of CCK in the activity of the endogenous opioid system. As in other experimental paradigms, CCK(A) and CCK(B) receptor stimulation appears to have opposite effects in modulating opioidergic activity.

Animals↗
PubMed1997

The effects of cholecystokinin A and B receptor antagonists on exploratory behaviour in the elevated zero-maze in rat.

The aim of the present study was to investigate the effects of cholecystokinin (CCK) CCK(A) and CCKB receptor antagonists SR 27897 B, devazepide, L 365260 and PD 135158 (CAM 1028) on exploratory behaviour in the elevated zero-maze in the rat. For further validation of the elevated zero-maze, the effects of a reference anxiolytic diazepam (0.25, 0.5, 1.0, 2.0 mg/kg), a non-benzodiazepine (BDZ) anxiolytic buspirone (0.04, 0.2, 1.0, 5.0 mg/kg), BDZ receptor inverse agonists FG 7142 (5, 10, 15, 20 mg/kg) and DMCM (0.1, 0.5, 1.0, 1.5 mg/kg), and a BDZ receptor antagonist flumazenil (10 mg/kg) were studied. Diazepam decreased the number of stretched-attend postures in all doses used and increased the percentage of time spent exploring in open parts at doses of 0.5 and 1.0 mg/kg. The effects of diazepam were blocked by flumazenil. FG 7142 and DMCM had effects only in subconvulsive doses (20 mg/kg and 1.5 mg/kg). Flumazenil and buspirone failed to show any effect. The CCK(A) receptor antagonists were also without any effect. The CCK(B) receptor antagonists L 365260 (1.0 and 5.0 mg/kg) and PD 135158 (100 microg/kg) had a significant anxiolytic-like effect. The CCK(B) receptor antagonists increased the number of open part entries, the number of head dips, the percentage of time spent exploring in the open part and decreased the number of stretched-attend postures. These data support the hypothesis of the involvement of the CCK(B) receptor subtype in the neurobiological mechanisms of anxiety.

Animals↗
PubMedDate not supplied

The effects of CCK-4 on dopamine D1 agonist-induced grooming are blocked by a CCK(A) receptor antagonist: evidence for a novel CCK receptor subtype?

The neuropeptide cholecystokinin (CCK) has been shown to interact with dopamine in various ways, including attenuation of dopamine D1 receptor-mediated vacuous chewing and grooming. While we have demonstrated a clear role for the CCK(A) receptor in the attenuation of dopamine D1 agonist-induced vacuous chewing, studies of grooming yielded anomalous results. We examined the effects of selective CCK receptor antagonists on the attenuation of SKF 38393-induced grooming by the CCKB agonist CCK-4. Administration of SKF 38393 (5 mg/kg s.c.) to male Sprague-Dawley rats resulted in a significant increase in grooming which was reduced to control levels by CCK-4 (20 mg/kg i.p.). Pretreatment with either the CCKA receptor antagonist devazepide or the CCK(B) receptor antagonist L-365,260 significantly attenuated this effect over a range of doses (20, 100, 500 microg/kg i.p.). The suppression of dopamine D1 agonist-induced grooming by CCK-4 does not appear to reflect a non-specific effect of anxiogenesis, as it was unaffected by the anxiolytic diazepam. The CCK receptor antagonists alone were without behavioural effect. Taken together with previous studies in models of anxiety and analgesia, our findings lend further support to the hypothesis that CCK-4 may act at a novel receptor subtype.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1997

Preloads of corn oil inhibit independent ingestion on postnatal day 15 in rats.

The ontogenetic development of postingestive inhibitory control of ingestion by an oil preload was examined in preweaning rats. Gastric preloads (5% b.wt) of water, mineral oil or corn oil were administered 5 min before a 30-min intake test in which pups licked milk from the floor of a test chamber. Preloads of corn oil decreased intake significantly compared with preloads of mineral oil or water on Postnatal Days 15 and 18, but not on Postnatal Day 12. Because preloads of corn oil reduced intake ore than preloads of mineral oil, it is possible that the inhibitory effect of corn oil is due to its fats rather than to its oily texture. Cholecystokinin (CCK), presumably released from the small intestine, apparently mediates part of this inhibitory effect because pretreatment with devazepide, a specific CKKA antagonist, significantly reduced the inhibition produced by corn oil.

Age Factors↗
PubMed2000

2-NAP, a peripheral CCK-A receptor antagonist, modulates the development of a preference for the mother by the newborn lamb.

The aim of this study was to investigate the effect of devazepide (DEV), a cholecystokinin (CCK)-A receptor antagonist, which crosses the blood-brain barrier (BBB) and prevents the development of a preferential relationship with the dam, and compare it to that of 2-NAP, which acts peripherally. At birth, lambs received either an intraperitoneal injection of saline (CTL), DEV (0.1 mg/kg), or 2-NAP (0.01, 0.1, or 1 mg/kg). No major side effects were observed after the injection, however, there was a trend for lambs receiving CCK-A antagonists to be more vocal in the first 2 h and to loose more weight between birth and 3 h. When tested in a two-choice test situations at 24 h of age, the latency to reach a ewe and the total time spent next to them were not affected by the treatments. On the other hand, unlike CTLs, lambs receiving DEV or 0.1 mg of 2-NAP did not spend significantly more time near their dam than near the alien ewe. 2-NAP had no effect at 0.01 mg/kg, but at 1 mg/kg, it improved the preference score. There was no relationship between preference scores and the variations in weight recorded during the neonatal period. The effects of DEV, but not those of 2-NAP, persisted at 48 h of age. Thus, these results support the hypothesis that peripheral CCK receptors are involved in the development of a preference for the mother, but the effects differ according to the amount of 2-NAP that the lambs receive.

Animals↗
PubMed1999

CCK(A) and 5-HT3 receptors interact in anorectic responses to amino acid deficiency.

Serotonin3 (5-HT3) receptors in the periphery mediate anorectic responses to the amino acid deficiency, which occurs after eating amino acid-imbalanced diets (IMB). However, other neurochemical systems, notably cholecystokinin (CCK), are known to affect food intake. We pretreated rats systemically with tropisetron, a 5-HT3 receptor antagonist, alone and combined with antagonists of CCK(A) and CCK(B) receptors, and measured intake of an IMB. Devazepide, a CCK(A) receptor antagonist, appeared to interact with tropisetron in the anorectic responses to IMB, blunting the usual remediation of IMB anorexia by tropisetron. The CCK(B) receptor antagonist, L-365, 260, increased intake of both IMB and an amino acid-balanced basal diet (BAS) and did not interact with tropisetron. Our data suggest that activation of CCK(A) receptors is interactive with 5-HT3 receptor activity in mediating IMB anorexia in the aminoprivic feeding model.

Amino Acids↗
PubMed1999

DA1 receptor activity opposes anorectic responses to amino acid-imbalanced diets.

The serotonin3 (5-HT3) receptor plays an important role in the aminoprivic feeding model. Other neurochemical systems, including cholecystokinin (CCK) and dopamine (DA), are known to affect food intake. We pretreated rats systemically with tropisetron, a 5-HT3 receptor antagonist, alone and combined with antagonists of DA1 and DA2 receptors, and measured intake of an amino acid-imbalanced diet (IMB). As expected, tropisetron significantly increased intake of IMB. SCH-23390, a DA1 antagonist, increased IMB anorexia. When combined with tropisetron, DA2 antagonism with eticlopride reduced short-term intake of both the basal diet (BAS) and IMB. In the IMB model, specificity of 5-HT3-DA2 interactions, and of 5-HT3-CCK(A) interactions from previous studies, prompted investigation of CCK(A)-DA2 interactions; there appeared to be none. SKF-38393, a DA1 agonist, combined with the CCK(A) receptor antagonist, devazepide, increased BAS and tended to increase IMB intake. Thus, CCK(A)-DA1 interactions were not specific for IMB. These data suggest that DA1 receptor activity opposes IMB anorexia, possibly via an interaction with the 5-HT3 receptor.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2003

Molecular cloning of an unusual bicistronic cholecystokinin receptor mRNA expressed in chicken brain: a structural and functional expression study.

This report describes the molecular cloning and pharmacological characterization of a transiently expressed chicken brain cholecystokinin receptor (CCK-CHR) in COS-7 cells. A polymerase chain reaction (PCR)-based cloning strategy was applied using: (1) an initial PCR with deoxyinosine-containing primers designed to target conserved regions in CCK receptors, followed by (2) rapid amplification of cDNA ends (RACE), and (3) full-length PCR of the CCK-CHR cDNA. The full-length cloned bicistronic CCK-CHR cDNA contained a short upstream open reading frame (uORF) coding for a putative six-amino-acid-long peptide of unknown function, followed by a long open reading frame (lORF) encoding the 436-amino-acid-long CCK-CHR receptor protein. At the amino acid level, the CCK-CHR shared approximately 50% homology with mammalian and Xenopus laevis CCK receptors. The pharmacological profile of CCK-CHR resembled that of CCK-B receptors using agonists (CCK-8, CCK-4, gastrin-17), whereas CCK-CHR showed higher affinity for the CCK-A receptor antagonist, devazepide, than for the CCK-B receptor antagonist, L-365,260. To the best of our knowledge, this is the first description and functional expression study of a cloned chicken CCK receptor cDNA.

Amino Acid Sequence↗
PubMed1999

PYY immunoneutralization does not alter lipid-induced inhibition of gastric emptying in rats.

UNLABELLED: PYY is released from the distal ileum by fat and may be involved in mediating lipid-induced inhibition of gastric acid secretion and intestinal motility. The role of PYY in intestinal lipid-induced inhibition of gastric emptying in awake rats was investigated using a specific polyclonal antibody raised against PYY. METHODS: Gastric emptying of liquids was measured in awake rats fitted with a Thomas gastric cannula. Intralipid (total dose 50 or 100 mg) was perfused for 10 min (0.05 ml/min) into a duodenal (n = 11) or mid-intestinal cannula (60 cm from Ligament of Treitz; n = 8), and gastric emptying was measured over the 5-10 min period. Gastric emptying was measured 15 min after IP injection of PYY (1 nmol/rat). PYY antibody (20 mg) or a control antibody (anti-KLH; keyhole limpet hemocyanin) was injected ip 8-12 h before experiments. RESULTS: Exogenous PYY (1 nmol) inhibited gastric emptying and administration of PYY antibody blocked this response. Perfusion of lipid (50 and 100 mg) into the proximal intestine produced a 46% and 66% inhibition of gastric emptying respectively. Inhibition of gastric emptying in response to 50 mg lipid in the proximal small intestine was unaffected by administration of PYY antibody but was abolished by administration of the CCK A receptor antagonist devazepide (0.1 mg/kg ip). Perfusion of lipid into the distal intestine (50 and 100 mg) inhibited gastric emptying by 10% and 32% respectively. Inhibition of gastric emptying in response to 100 mg lipid in the distal intestine was unaffected by PYY antibody. CONCLUSIONS: Lipid perfused into either the proximal or distal intestine inhibits gastric emptying via a PYY-independent mechanism. CCK is involved in proximal lipid induced inhibition of gastric emptying.

Animals↗
PubMed2000

Caseinomacropeptide specifically stimulates exocrine pancreatic secretion in the anesthetized rat.

The effect of caseinomacropeptide (CMP) (the [106-169] fragment of kappa-casein produced during digestion of milk protein), was studied in anesthetized rats using bile diversion for a pure pancreatic juice collection system. Intraduodenal administration of CMP induced a dose-related specific stimulation of pancreatic secretion which was nearly abolished by devazepide, atropine, hexamethonium, vagotomy or perivagal capsaicin pretreatment. Moreover, CMP did not inhibit in vitro trypsin activity. These results demonstrate that CMP is more likely to stimulate pancreatic secretion specifically through cholecystokinin release and activation of a vago-vagal cholinergic reflex loop than by inhibition of luminal trypsin, in anesthetized rats.

Anesthesia↗
PubMed2001

Attenuated satiation response to intestinal nutrients in rats that do not express CCK-A receptors.

Pharmacological experiments suggest that satiation associated with intestinal infusion of several nutrients is mediated by CCK-A receptors. Otsuka Long-Evans Tokushima Fatty, (OLETF), rats do not express CCK-A receptors and are insensitive to the satiation-producing effects of exogenous CCK. To further evaluate the role of CCK-A receptors in satiation by intestinal nutrient infusion, we examined intake of solid (pelleted rat chow) or liquid (12.5% glucose) food intake, following intestinal infusions of fats (oleic acid or fat emulsion), sugars (maltotriose or glucose), or peptone in OLETF rats and Long Evans Tokushima Otsuka control rats (LETO). Intestinal infusion of glucose or maltotriose reduced solid food intake more in LETO than in OLETF rats from 30 min through 4 h post infusion. Reduction of solid food intake by intestinal infusions of fat or peptone did not differ between OLETF and LETO rats during the first 30 min post infusion, but reduction of intake by these infusates was attenuated in OLETF rats over the ensuing 4h post infusion. Intestinal infusion of glucose, oleate, fat emulsion and peptone reduced 30-min intake of 12.5% glucose more in LETO than OLETF rats. Furthermore, pretreatment with the CCK-A receptor antagonist, devazepide, attenuated intestinal nutrient-induced reduction of food intake only in LETO, but not OLETF rats. Our results confirm pharmacological results, indicating that CCK-A receptors participate in satiation by nutrients that elevate plasma CCK concentrations, as well as by nutrients that do not stimulate secretion of endocrine CCK. In addition, our results indicate: 1) that OLETF rats have deficits in the satiation response to a variety of intestinal nutrient infusions; 2) that the temporal pattern for CCK-A receptor participation in satiation by intestinal nutrients is different during ingestion of liquid and solid foods and 3) that intestinal nutrients provide some satiation signals that are CCK-A receptor mediated and some that are not.

Animals↗
PubMed1997

Endogenous CCK in the control of gastric emptying of glucose and maltose.

A role for endogenous cholecystokinin (CCK) in the control of gastric emptying of liquid glucose and maltose test meals in rhesus monkeys was assessed. Intragastric administration of a dose range (10-100 micrograms/kg) of the CCKA receptor antagonist devazepide produced a dose dependent acceleration of the emptying of 100 ml 300 mOsm test meals of glucose and maltose but had no effect on the emptying of a hyperosmotic (750 mOsm) NaCl solution. At the 100 micrograms/kg dose, the emptying of glucose and maltose meals were as rapid as the emptying of physiological NaCl. These data expand the demonstrated role of endogenous CCK in the slowing of gastric emptying of nutrients in rhesus monkeys to carbohydrates and suggest that previous negative results were due to the hyperosmotic nature of the glucose solutions.

Animals↗
PubMed1997

Prolonged intestinal afferent nerve discharge in response to cholecystokinin-58 compared to cholecystokinin-8 in rats.

Intestinal afferents are sensitive to cholecystokinin (CCK) octapeptide. However, CCK-58 may be a more biologically relevant molecule. Therefore, recordings from jejunal mesenteric afferent bundles were secured for extracellular multi-unit recording and the responses to CCK-8 and CCK-58 compared. CCK-8 and CCK-58 (i.v.) evoked a dose-dependent, devazepide sensitive, increase in afferent nerve discharge. Peak discharge frequency was higher for CCK-8 at all doses (P < 0.05). However, response duration was more prolonged for CCK-58 (P < 0.05) at 200 pmol.kg(-1). This resulted in an overall increase in area under the curve of CCK-58 compared to CCK-8 (P < 0.05). CCK-58 stimulates afferent discharge in a different pattern than CCK-8 and, therefore, may have differential biological effects.

Afferent Pathways↗
PubMed1998

The role of endogenous cholecystokinin in the sensory transduction of luminal nutrient signals in the rat jejunum.

Some vagal afferent fibres are exquisitely sensitive to exogenous administration of cholecystokinin (CCK) but their sensitivity to endogenous CCK released by luminal stimuli has not been demonstrated directly, although implied from reflex and behavioural studies. We have therefore utilised electrophysiological techniques to record afferent discharge in mesenteric nerve bundles supplying the rat jejunum in response to luminal application of casein acid hydrolysate (CAH). CAH stimulated whole nerve afferent discharge in both in vivo and in vitro preparations (P < 0.01) while single unit analysis revealed that fibres sensitive to CAH also responded to exogenous CCK. The responses to both CCK and CAH were abolished by the CCKA antagonist devazepide. This study therefore supports the hypothesis that a functional relationship exists between CCK-containing enteroendocrine cells and the afferent fibres whose terminals lie within close proximity.

Afferent Pathways↗