The cholecystokinin receptor antagonist L364,718 increases food intake in the rat by attenuation of the action of endogenous cholecystokinin

Abstract

To determine the role of endogenous cholecystokinin (CCK) in the regulation of food intake, the effects of the potent CCK receptor antagonist L364,718 were investigated on the intake of a palatable diet in non‐deprived rats. The effect of a single dose of proglumide was also investigated for comparative purposes. In addition, the ability of L364,718 to antagonize the reduction in food intake produced by exogenous cholecystokinin‐octapeptide (CCK8) or bombesin in food‐deprived rats was determined. L364,718 (10–100 μg kg−1, i.p.) increased the intake of palatable diet during the 30 min test period. Proglumide (300 mg kg−1, i.p.) also increased the intake of palatable diet. Conversely, CCK8 (0.5–5 μg kg−1, i.p.) produced a reduction in the intake of the diet. In fasted rats, L364,718 (100 μg kg−1, i.p.) antagonized the reduction in food intake produced by CCK8 (10 μg kg−1, i.p.) but not that produced by bombesin (50 μg kg−1, i.p.). L364,718 did not increase food intake in these animals when measured over a 6 h period. It is concluded that L364,718 is a potent, selective antagonist of the effects of CCK8 on food intake. The observation that L364,718 and proglumide increase the intake of a palatable diet provides some evidence that endogenous CCK is involved in the control of food intake in this model.

Extrinsic primary afferent signalling in the gut

“…These include cholecystokinin (CCK), glucagon-like peptide 1 (GLP1), apolipoprotein A-IV, enterostatin, gastrin-releasing peptide (a member of the bombesin family), oxyntomodulin, amylin and peptide YY. CCK administration causes reduced food intake, 55 while antagonists to CCK A receptors substantially increase food intake; 56 thus, endogenous CCK has a role in controlling meal size. The satiety-inducing effects of CCK require an intact vagus nerve.…”

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

“…Furthermore, experiments with L-364,718 provided support for the physiologic significance of endogenous CCK-8 as a mediator of feeding behavior. Administration of L-364,718 alone to mice, rats, pigs, or monkeys increases food intake when assessed using a variety of feeding paradigms (7)(8)(9)(11)(12)(13). In addition, it was reported that L-364,718 enhanced hunger ratings in humans (14).…”

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

“…They were injected with 0, 10.0, 30.0 and 100.0 yg kg-1, respectively, of (Dourish et al, 1988b;Hewson et al, 1988;Reidelberger et al, 1988 (Neill & Cooper, 1989 (Cooper, 1986;Cooper et al, 1985a) to produce a suppression of palatable food intake similar to 3.0mg kg-' of ( + )-fenfluramine.…”

“…range of doses from 1 pg kg-1 to 10mg kg-1 (i.p. ), antago-nized the anorectic effect of CCK-octapeptide, but not of bombesin (Lotti et al, 1987;Dourish et al, 1988b;Hewson et al, 1988; Khosla & Crawley, 1988;Reidelberger et al, 1988).…”