Additive effects of cannabinoid CB1 receptors blockade and cholecystokinin on feeding inhibition

Cannabinoid CB1 receptor and cholecystokinin-1 (CCK₁) receptors are located in peripheral nerve terminals of the gut, where they mediate satiety signals. Here we describe a detailed analysis of the interaction of both receptors in the control of feeding of food-deprived rats. Male Wistar rats were deprived for food 24 h before testing. Rats were pre-treated with SR141716A (Rimonabant) or WIN 55,212-2 before CCK-8 sulphated administration and tested for food intake 60, 120 and 240 min after last drug injection. In parallel, the effect of Lorglumide - a CCK₁ receptor antagonist - pre-treatment was evaluated on feeding behaviour after SR141716A administration. Results show that SR141716A activates c-Fos expression in brainstem areas receiving vagal inputs. Blockade of CB1 receptors with SR141716A (1 mg/kg) reduces feeding and display additive satiety induction with the CCK₁ receptor agonist CCK-8 sulphated (5, 10, 25 μg/kg). The effect of SR141716A is not blocked by Lorglumide (10 mg/kg), indicating independent sites of action. Conversely, the administration of the CB1 agonist WIN 55,212-2 (2 mg/kg) reduced satiety induced by CCK-8. In conclusion, these results report additive anorectic actions for CCK1 activation and peripheral CB1 receptor blockade providing a framework for combined therapies in the treatment of eating disorders.