Preferential effects of the cannabinoid CB, receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats

Rationale: The selective CB1 receptor antagonist, SR 141716, has been demonstrated to reduce food consumption in a range of animal species. Objective: To assess the effect of chronic administration of SR 141716 on body weight and ingestive behaviour of lean and obese (fa/fa) Zucker rats. Methods: Lean and obese Zucker rats were orally dosed with SR 141716 (3, 10, 30 mg/kg PO), sibutramine (5 mg/kg PO) or vehicle for one week. Pair-fed controls provided insight as to whether the effect of SR 141716 on body weight was attributable to drug-induced hypophagia. Subsequently, the effect of chronic oral administration of SR 141716 (1, 3, 10 mg/kg) was assessed for 28 days. At the end of this period, all animals were given vehicle for 14 days. The incidence of wet-dog shakes, yawning, scratching, and grooming behaviours, was assessed after acute administration and at weekly intervals thereafter for 4 weeks. Results: SR 141716 dose-dependently decreased food intake and body weight gain in both lean and obese animals. The inhibition of food intake and body weight gain was greater in obese Zuckers than in lean Zucker controls. Changes in the body weights of pair-fed controls closely paralleled those of their drug-treated counterparts. Chronic 28-day treatment led to a maintained reduction of body weight gain. Withdrawal of SR 141716 on day 28 resulted in rebound hyperphagia and a significant weight gain. On acute administration, SR 141716 dose-dependently induced motor behaviours that showed tolerance upon repeated administration. Conclusion: These data indicate that chronic oral treatment with SR 141716 significantly reduces the food intake and body weight gain of obese and lean Zucker rats, an effect that is greater in obese animals and reversible upon drug withdrawal.