Reversal of the anorectic effect of (+)‐fenfluramine in the rat by the selective cholecystokinin receptor antagonist MK‐329

Abstract

1 Experiments were conducted to determine whether or not the effect of (+)-fenfluramine (3.0mgkg-, i.p.) on food intake can be antagonized by the selective cholecystokinin receptor antagonist MK-239 (formerly L364,718; (3S(-)-N42,3-dihydro-1-methyl-2-oxo-5-phenyl-1-H-1,4-benzodiazepin-3-yl)-1H-indole-2-carboxamide). Two feeding paradigms were employed. In the first, non-deprived rats were familiarized with eating a highly palatable, sweetened mash in a 30min test. In the second, freely-feeding rats were trained to consume powdered chow in their home-cages, and their intake was monitored over the first 6 h of the night-period. 2 In doses of 30.0 and 100.0Ougkg-', s.c., MK-329 almost completely blocked the anorectic effect of (+)-fenfluramine in the palatable food intake test. These doses of MK-329 have previously been reported to antagonize the anorectic effect produced by exogenous cholecystokinin-octapeptide (CCK8) in rats. Both doses of MK-329 were also effective in significantly attenuating the anorectic effect of (+)-fenfluramine in nocturnal free-feeding animals over a 6 h-period. 3 MK-329 (10.0-100.Ogkg-, s.c.) failed to antagonize the anorectic effect of either the specific dopamine D2-receptor agonist quinpirole (0.3mgkg-', s.c.) or the fi-carboline FG 7142 (10.Omgkg-1, i.p.) in the palatable food intake test. 4 MK-329 (10.0-300.Opgkg-1, s.c.) had no effect, when administered alone, on the level of palatable food intake in non-deprived rats, even when substantial satiation was produced by a pre-feeding procedure. Furthermore, MK-329 had no effect, when administered alone, on nocturnal food intake in freelyfeeding rats. 5 In conclusion, not only was MK-329 a potent antagonist of the effect of CCK8 on food intake, it also blocked the effect of (+)-fenfluramine to a significant degree. The effect of MK-329 was selective in that the anorectic effects of either quinpirole or FG 7142 remained unaffected. Administered alone, MK-329 did not affect food intake, indicating that its reversal of (+ -fenfluramine-induced anorexia was not secondary to an intrinsic hyperphagic effect. The results provide some evidence that the depressant effect of (+ )-fenfluramine on food intake depends on the activity of endogenous CCK.

Pharmacological evaluation of IQM‐95,333, a highly selective CCKAreceptor antagonist with anxiolytic‐like activity in animal models

“…The method of Cooper et al (1990) was used. Animals were allowed free access to food and they were given a palatable diet daily.…”

Serotonin controlling feeding and satiety

“…Cooper et al [230] took the opposite approach and investigated if 5-HT induced satiety would require CCK activity. They and others [231] demonstrated that the CCK1-receptor antagonist devazepide blocked the satiating effect of systemic 5-HT or fenfluramine, whereas the CCK2-recptor antagonist L-365.260 was ineffective.…”

The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight

“…In addition, it was reported that L-364,718 enhanced hunger ratings in humans (14). Despite the large body of evidence in support of endogenous CCK as a physiologic mediator of food intake, there are a considerable number of studies that have failed to detect a significant increase in feeding after L-364,718 administration (3,7,8,15,16). The physiologic variables and/or subtle differences in the feeding paradigms, which explain the discrepant findings with this CCK-AR-specific antagonist are currently unknown.…”