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Reversal of the anorectic effect of (+)‐fenfluramine in the rat by the selective cholecystokinin receptor antagonist MK‐329
Author(s) -
Cooper S.J.,
Dourish C.T.,
Barber D.J.
Publication year - 1990
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1990.tb14655.x
Subject(s) - anorectic , fenfluramine , cholecystokinin , endocrinology , medicine , chemistry , agonist , antagonist , cholecystokinin receptor , quinpirole , food intake , pharmacology , receptor , serotonin
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 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. 3 MK‐329 (10.0–100.0 μg kg −1 , s.c.) failed to antagonize the anorectic effect of either the specific dopamine D 2 ‐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. 4 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. 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.