Abstract
Cholecystokinin (CCK) is a peptide that is found throughout the brain and in neurons and endocrine cells of the gastrointestinal tract. Studies demonstrating that systemic administration of the CCK1 receptor antagonist devazepide increases food intake in a variety of species provide compelling evidence that CCK plays an essential role in producing the satiation that occurs with ingestion of a meal. Given that devazepide readily penetrates the blood-brain barrier, it remains to be determined whether endogenous CCK is acting peripherally, within the brain, or at multiple peripheral and central sites to produce satiety.|In this study we used the CCK2 receptor antagonist L365,265, and two different CCK1 receptor antagonists, devazepide, which freely crosses the blood brain barrier, and A70104, which does not, to further define the receptor subtype and site of action of endogenous CCK to produce satiety. Experiments were designed to 1) determine whether endogenous CCK acts at CCK1 or CCK2 receptors to inhibit food intake; 2) determine whether endogenous CCK acts as an essential satiety factor at different times across the diurnal cycle; and 3) determine whether endogenous CCK acts at CCK1 receptors central or peripheral to the blood brain barrier to produce satiety.|These experiments produced several new findings. First, IV injection of the CCK1 receptor antagonist devazepide at a dose that stimulates food intake in rats (1 mg kg‘1), had no effect on gastrin-induced stimulation of gastric acid secretion in rats, an action that is mediated by the CCK2 receptor, and that was blocked by the CCK2 receptor antagonist L365.260. This finding further supports the hypothesis that endogenous CCK acts at CCK1 receptors, not CCK2 receptors, to produce satiety. Second, IV injection of the CCK1 receptor antagonist devazepide significantly stimulated cumulative 4-h food intake at 0,16 and 20 h after dark onset by 31%, 54% and 40%, respectively, yet had no effect on food intake at 4, 8 or 12 h after dark onset. Devazepide-induced increases in food intake occurred through an increase in meal frequency not meal size. These results suggests that endogenous CCK plays an essential role in producing satiety in rats only during several hours before and after the onset of the dark period. It is likely that at other times of the day, a greater degree of redundancy in satiety signaling occurs such that CCK receptor blockade produces little if any effect. Third, IV infusion of the CCK1 receptor antagonist A- 70104 (1000 nmol kg'1 h'1) for 3 h during the early dark period completely reversed the 70% reduction in food intake produced by a maximal 3-h inhibitory dose of CCK-8 (10 nmol kg'1 h"1 IV). In contrast, this dose of A-70104 had no effect on food intake when administered alone under the same conditions in which devazepide (1 mg kg'1 IV) increased food intake by more than 50%. A-70104 (1000 nmol kg'1 h'1) also did not reverse the 40% reduction in food intake produced by a 2-h duodenal infusion of oleic acid (460 Jmol h'1), an effect that was completely reversed by devazepide. Because devazepide readily penetrates the blood brain barrier, while A-70104 does not, these results suggest that endogenous CCK produces an essential satiety action mediated by CCK1 receptors located in brain regions beyond the blood-brain barrier.