REVERSAL OF THE ANORECTIC EFFECT OF (+)-FENFLURAMINE IN THE RAT BY THE SELECTIVE CHOLECYSTOKININ RECEPTOR ANTAGONIST MK-329

Experiments were conducted to determine whether or not the effect of (+)-fenfluramine (3.0 mg kg-1, i.p.) on food intake can be antagonized by the selective cholecystokinin receptor antagonist MK-239 (formerly L364,718; (3S(-)-N-(2,3-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 30 min 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. In doses of 30.0 and 100.0 μg kg-1, 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. MK-329 (10.0-100.0 μg kg-1, s.c.) failed to antagonize the anorectic effect of either the specific dopamine D2-receptor agonist quinpirole (0.3 mg kg-1, s.c.) or the β-carboline FG 7142 (10.0 mg kg-1, i.p.) in the palatable food intake test. MK-329 (10.0-300.0 μg kg-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 freely-feeding rats. 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.