The cannabinoid CB1 antagonist AM 251 produces food avoidance and behaviors associated with nausea but does not impair feeding efficiency in rats

Rationale: A growing body of evidence suggests that cannabinoid CB1 receptor antagonists have potential therapeutic utility as appetite suppressants. However, the specific mechanisms underlying the reduction in food intake produced by these drugs are not well understood. Objective: Considering the known antiemetic and motor-suppressive effects of CB1 agonists, the present studies were conducted to determine if the reductions in food intake induced by the CB1 antagonist AM 251 could result from nausea or impairments in intake-relatedmotor control, rather than solely from appetite suppression. Methods: Three experiments were conducted to examine the effects of AM 251 (2.0, 4.0, or 8.0 mg/kg or vehicle) on detailed parameters of food intake, on the development of conditioned taste avoidance, and on taste reactivity. Results: In the first experiment, acute administration of AM 251 dose-dependently decreased food intake; nevertheless, feeding rate ( grams consumed per time spent eating) and food handling were unaffected, which suggests that food intake was not reduced because of severe motor impairments. In the second experiment, AM251 dose-dependently reduced intake of a flavor with which it had previously been associated, indicating that conditioned taste avoidance had developed. Lastly, AM 251 was found to induce conditioned rejection reactions in a dose-dependent manner. Conclusions: The CB1 antagonist AM 251 may reduce food intake in part by inducing nausea or malaise, but not because of incoordination or motor slowing related to feeding.