Cannabinoid (CB)1 receptor antagonist, AM 251, causes a sustained reduction of daily food intake in the rat

Cannabinoid (CB), receptors are present throughout the nervous system, including several areas implicated in the control of food intake. Central and peripheral administration of CB1 agonists increase food intake while CB1 receptor antagonists reduce food intake. However, in some previous studies, tolerance to the anorectic effects of CB1 antagonists develops within days. To further delineate the role of endogenous cannabinoid signaling in energy intake, we studied the effects of the CB1 antagonist AM 251 (1.25, 2.5 and 5 mg/kg ip), the anandamide membrane transporter inhibitor VDM 11 (10 mg/kg ip), and the CB1 agonists anandamide (1 mg/kg ip), and methanandamide (1 mg/kg ip), on food intake. A single administration of the CB1 antagonist AM 251 significantly reduced food intake for a total of 6 days (P<.05). Reductions in food intake brought about by AM 251 were accompanied by reductions in weight gain for 6 days (P<.05). Contrary to expectations, VDM 11 did not increase food intake in this study. Anandamide was also unable to increase food intake; however, the more stable agonist methanandamide significantly increased food intake 3 h after administration (P<.05). These results support the role of CB1 receptor antagonists in the treatment of obesity and suggest that the anorectic effect of AM 251 may last longer than previously reported. (C) 2004 Elsevier Inc. All rights reserved.