Reversal of the anorectic effect of (+)-fenfluramine in the rat by the selective cholecystokinin receptor antagonist MK-329.
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.
Cooper
S J
SJ
School of Psychology, University of Birmingham.
Dourish
C T
CT
Barber
D J
DJ
D000818:Animals; D001067:Appetite Depressants; D001570:Benzodiazepinones / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D002766:Cholecystokinin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020109:Devazepide; D004435:Eating / Q000187:drug effects; D004873:Ergolines / Q000494:pharmacology; D005277:Fenfluramine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D019257:Quinpirole; D051381:Rats
D001067:Appetite Depressants; D001570:Benzodiazepinones; D002243:Carbolines; D004873:Ergolines; D019257:Quinpirole; D005277:Fenfluramine; C035874:FG 7142; D002766:Cholecystokinin; D020109:Devazepide