Peptides, Vol. 12, pp. 1215-1221.Pergamon Press plc, 1991. Printed in the U.S.A. 0196-9781/91 $3.00 + .00 Effects of Selective Cholecystokinin Antagonists L364,718 and L365,260 on Food Intake in Rats ROGER D. REIDELBERGER,I GABOR VARGA AND TRAVIS E. SOLOMON Research Service, VA Medical Center, Omaha, NE 68105 Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178 Institute of Experimental Medicine, H-1450 Budapest, Hungary Research Service, VA Medical Center, Kansas City, MO 64128 Departments of Medicine and Physiology, Kansas University Medical Center, Kansas City, KS 66103 Received 5 July 1991 REIDELBERGER, R. D., G. VARGA AND T. E. SOLOMON. Effects of selective cholecystokininantagonists L364,718 and L365,260 on food intake in rats. PEFrlDES 12(6) 1215-1221, 1991.--The selective type A and B cholecystokinin (CCK) recep- tor antagonists L364,718 and L365,260 were used to identify the receptor subtype that mediates the satiety effect of endogenous CCK. Male rats (n = 12-13/group), fed ground rat chow ad lib, received L364,718 (0, 1, 10, 100, or 1000 p,g/kg IP) or L365,260 (0, 0.1, 1, 10, 100, 1000, or 10,000 p.g/kg IP) 2 h after lights off, and food intake was measured 1.5, 3.5, and 5.5 h later. L364,718 significantly stimulated 1.5-h food intake by more than 40% at 10 p.g/kg and higher doses; cumulative intake at 3.5 and 5.5 h remained elevated by about 20% at 1000 and 100 ~.g/kg of L364,718, respectively. In contrast, L365,260 had no significant stimulatory effect on feeding at any dose. The potency of L365,260 for antagonizing gastrin-stimulated gastric acid secretion was examined in unanesthetized rats. Male rats (n = 14), prepared with gastric and jugular vein cannulas, received doubling doses of gastrin (G-17I) (0.16-5 nmol/kg/h IV), each dose for 30 min, and gastric juice was collected for each 30-min period. G-17I stimulated gastric acid output dose dependently; the minimal effective dose was 0.16 nmol/kg/h, while maximal output (5-fold above basal) occurred at 5 nmol/kg/h. L365,260 (0, 1, 10, 100, 1000, or 10,000 p.g/kg IV), administered 30 min before continu- ous infusion of G-17I (1.25 or 5 nmol/kg/h), significantly inhibited acid output only at 10,000 p.g/kg; cumulative 60-rain output was decreased by 60%. These results suggest that CCK acts at CCK-A receptors to produce satiety during the dark period in ad lib-feeding rats. Cholecystokinin receptors Gastric acid secretion Gastrin Satiety Feeding behavior Appetite regulation THE recent development of potent and specific CCK receptor antagonists provides a means to investigate the importance of endogenous CCK in control of feeding behavior. Several studies have now demonstrated that peripheral administration of L364,718 (also known as MK-329 or devazepide), an antagonist selective for the type A receptor (CCK-A), increases food intake in sev- eral species (9, 10, 13, 31, 36), thus providing strong evidence for a physiological role for CCK in producing satiety. Dourish et al. (9) have recently reported that L365,260, an antagonist selective for the type B receptor (CCK-B) (3,24), is 100 times more potent than L364,718 in increasing food intake in partially satiated rats, suggesting that endogenous CCK acts at the CCK-B rather than the CCK-A receptor subtype to produce satiety. Studies of the effects of CCK agonists on food intake do not support this conclusion, however. CCK-8, an agonist with simi- lar affinities for CCK-A and CCK-B receptors, suppresses feed- ing in several species after central or peripheral administration (2,34). In contrast, neither central (2, 7, 34) nor peripheral ad- ministration (1,2) of selective CCK-B receptor agonists [nonsul- fated CCK-8 (2,34), gastrin (2), CCK-4 (2), and BC 264 (1,7)] has been shown to affect food intake. Thus the receptor subtype mediating the satiety effect of endogenous CCK has not been clearly identified. We have previously characterized the potency and efficacy of L364,718 for antagonizing the effects of exogenous CCK-8 on food intake (31) and pancreatic exocrine secretion (28) in unanesthetized rats. Because L365,260 does not differentiate be- tween CCK-B and gastrin receptors (24), in the present study we assessed the potency and efficacy of L365,260 antagonism in vivo by determining the dose-dependent effects of L365,260 on gastrin-stimulated gastric acid secretion in unanesthetized rats. To investigate the role of type A and B CCK receptors in control of feeding behavior, we compared the dose-dependent effects of L364,718 and L365,260 on food intake during the dark period in ad lib-feeding rats. Results of feeding studies have been presented previously in abstract form (32). METHOD Dose-Response Effects of L365,260 and L364, 718 on Food Intake Seventy-four male Sprague-Dawley rats (Sasco, Omaha, NE) were maintained at constant temperature (24 °) on a reversed mRequests for repdnts should beaddressedtoRoger D. Reidelberger, Ph.D.,Research Service (151),Omaha VAMedical Center, 4101Woolworth Avenue, Omaha, NE68105. 1215