Intracerebroventricular administration of cannabinoid CB1 receptor antagonists AM251 and AM4113 fails to alter food-reinforced behavior in rats

Drugs that interfere with cannabinoid CB1 transmission suppress food-motivated behaviors and may be useful as appetite suppressants, but there is uncertainty about the locus of action for the feeding-suppression effects of these drugs. The present work was conducted to determine if two drugs that interfere with cannabinoid receptor transmission, AM251 and AM4113, have effects on food-reinforced behavior after administration into the lateral ventricle (intracerebroventricular (ICV)). Although systemic administration of both drugs can suppress food-reinforced behavior, neither AM251 (40, 80, and 160 mu g) nor AM4113 (60, 120, and 240 mu g) administered at various times prior to testing produced any suppression of food-reinforced operant responding on a fixed-ratio 5 schedule. Because the modulation of locomotion by drugs that act on CB1 receptors is hypothesized to be a forebrain effect, these drugs also were assessed for their ability to reverse the locomotor suppression produced by the CB1 agonist AM411. ICV administration of either AM251 or AM4113 reversed the locomotor suppression induced by the CB1 agonist AM411 in the same dose range that failed to produce any effects on feeding. This indicates that both AM4113 and AM251, when administered ICV, can interact with forebrain CB1 receptors and are efficacious on forebrain-mediated functions unrelated to feeding. These results suggest that CB1 neutral antagonists or inverse agonists may not be affecting food-reinforced behavior via interactions with forebrain CB1 receptors located in nucleus accumbens or hypothalamus and that lower brainstem or peripheral receptors may be involved.