Pretreatment with subeffective doses of Rimonabant attenuates orexigenic actions of orexin A-hypocretin 1

Recent studies suggest that blockade of cannabinoid CB I receptors suppresses feeding, an effect observed in humans treated with the cannabinoid CB I antagonist Rimonabant. A cross-talk between cannabinoids and other systems controlling appetite might exist since cannabinoid receptors are present in hypothalamic neural circuits involved in feeding regulation and energy expenditure. Orexin A-hypocretin 1, an orexigenic peptide, is an ideal candidate to interact with cannabinoid receptors. Both of them play an important role in feeding and they co-localize in similar brain regions. To study this hypothesis we investigated (a) the effects on food intake of either orexin A-hypocretin I or the cannabinoid CB1 receptor antagonist Rimonabant in pre-fed rats, and (b) the interaction between them by monitoring the effects of the combined administration of cannabinoids and orexin A-hypocretin I in pre-fed rats. The results show that (1) orexin A-hypocretin I is a short-term modulator of appetite that increases food intake in pre-fed rats, (2) Rimonabant decreases food intake and (3) such effective and subeffective doses of Rimonabant block the orexigenic effect of orexin A-hypocretin 1. The results support the idea that cannabinoid and orexin A-hypocretin I systems share a common mechanism in food intake and indicate that the hypothalamic orexigenic circuits are involved in cannabinoid CB1 receptor antagonism-mediated reduction of appetite. (c) 2007 Elsevier Ltd. All rights reserved.