We examined the roles of cholecystokinin (CCK)-2 receptors in the regulation of pepsinogen secretion in the CCK-1 receptor deficient Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Pepsinogen secretion was determined in fasted acute fistula OLETF and control Long-Evans Tokusima Otsuka (LETO) rats. Pepsinogen secretion in OLETF rats under basal conditions as well as in response to CCK-8 stimulation was significantly higher than that in LETO rats. CCK-1 receptor specific agonist ARL 15849 was unable to stimulate pepsinogen secretion in OLETF rats, whereas it elicited pepsinogen secretion in LETO rats to levels similar to those obtained with equimolar CCK-8 stimulation. CCK-2 receptor antagonist reduced basal pepsinogen secretion and completely abolished CCK-8-stimulated pepsinogen output in OLETF rats, whereas in LETO rats, it reduced basal pepsinogen secretion but augmented CCK-8-stimulated pepsinogen output. CCK-1 receptor antagonist loxiglumide also greatly decreased CCK-8-stimulated pepsinogen secretion in OLETF rat, which indicates that loxiglumide is not a specific CCK-1 receptor antagonist. Intravenous infusion of somatostatin antagonist significantly increased CCK-8-stimulated pepsinogen secretion in LETO rats, whereas it had no significant influence on CCK-8-stimulated pepsinogen secretion in OLETF rats. These results indicate that CCK-8 stimulates pepsinogen secretion via CCK-2 receptors in CCK-1 receptor deficient OLETF rats and that the higher CCK-8-stimulated as well as basal pepsinogen secretion in OLETF rats might result from an elimination of tonic inhibition by somatostatin that is released from D cells through mainly CCK-1 receptors.

1999-03-01·Pharmacology Biochemistry and Behavior4区 · 心理学

Behavioral Effects of AR-R 15849, a Highly Selective CCK-A Agonist

4区 · 心理学

Article

作者: T.J Hudzik ; F.C Kaiser ; R.D Simmons

The behavioral effects of AR-R 15849, a novel cholecystokinin agonist with high affinity and selectivity for the CCK-A receptor subtype, were examined. Initially, using an operant feeding paradigm to test for anorectic activity and specificity, acute administration of AR-R 15849 was found to alter the intake and pattern of feeding in a manner similar to prefeeding. Further, AR-R 15849 did not induce compensatory feeding as did CCK-8, and did not affect performance on running rates of responding, or motor activity on a running wheel, as did fenfluramine. In tests for subchronic anorectic activity, daily intraperitoneal injections of AR-R 15849 significantly reduced food intake in fasted rats over a 9-day test period with greater efficacy compared to its nonselective predecessor AR-R 14294 (formerly FPL 14294). The sustained decrease in food intake with AR-R 15849 treatment resulted in a significant reduction in body weight gain over 9 days. Finally, an experiment designed to determine the effect of caloric deprivation and subchronic drug exposure on the overall efficacy of AR-R 15849 indicated that pharmacological tolerance does not develop following subchronic treatment.

1998-02-01·Pharmacology Biochemistry and Behavior4区 · 心理学

ARL 15849: A Selective CCK-A Agonist With Anorectic Activity in the Rat and Dog

4区 · 心理学

Article

作者: J.R Rosamond ; F.C Kaiser ; Roy D Simmons ; M.E Pierson

Cholecystokinin octapeptide (CCK-8) and the peptide analog ARL 14294, formerly FPL 14294, [Hpa(SO3H)-Met-Gly-Trp-Met-Asp-N(Me)Phe-NH2], have been reported to induce satiety by interaction with the CCK-A receptor subtype. ARL 15849 [Hpa(SO3H)-Nle-Gly-Trp-Nle-N(Me)-Asp-Phe-NH2] is an improved ARL 14294 analog with enhanced CCK-A receptor selectivity, greater stability, and a longer duration of action. The affinity of ARL 15849 for the CCK-A receptor (Ki = 0.034 nM) is 6,600 fold greater than for the CCK-B receptor (Ki = 224 nM), whereas CCK-8 and ARL 14294 are nonselective. Although comparable in potency to contract isolated gallbladder and induce pancreatic phosphatidylinositol hydrolysis, ARL 15849 is 3- and 100-fold more potent than ARL 14294 and CCK-8, respectively, to inhibit 3-h feeding in rats. The duration of feeding inhibition was significantly longer for ARL 15849 (>5 h), compared to equipotent doses of ARL 14294 (3 h), and CCK-8 (1 h). Intranasal administration of ARL 15849 inhibits feeding in beagle dogs with a greater separation between doses that induce emesis and those that inhibit feeding. Therefore, ARL 15849 is a potent, selective, intranasally active anorectic agent which may be useful in the treatment of eating disorders.

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