Endocannabinoids (anandamide and 2-AG) are relevant modulators of appetite and energy expenditure through their action on cannabinoid CB1 receptors. The actions of anandamide on feeding behavior are dependent both, on the anatomical location of CB1 receptors (central nervous system versus peripheral tissues) and the feeding status. Anandamide uptake into cells, prior to its degradation by specific enzymatic systems, is a necessary step for the regulation of its extracellular levels. The present study explores the route and feeding stimulus dependency of the effects of the anandamide uptake blocker AM404. Peripherally, AM404 reduced feeding in partially satiated animals through a PPARα-independent mechanism, but not in food deprived ones. When AM404 was injected into the cerebral ventricles of food deprived rats, it resulted in hyperphagia that was antagonized by the cannabinoid receptor inverse agonist SR141716A. These results support the multimodal action of endocannabinoid signaling in feeding regulation, which depends on the anatomical site and the feeding status of the animal.Highlights
▸ Examination of the anandamide uptake blocker AM404 on feeding in fast and satiation. ▸ AM404 (i.p.) is anorectic in partially satiated rats via PPARα-independent mechanisms. ▸ AM404 (i.c.v.) induces appetite in fasted rats, and this effect is abolished by SR141716A (i.p.). ▸ We show the multimodal action of the endocannabinoid signaling on feeding regulation.