1. 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. 2. In doses of 30.0 and 100.0 micrograms 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. 3.
MK-329 (10.0-100.0 micrograms 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
beta-carboline FG 7142 (10.0 mg kg-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.