Involvement of the hypocretin/orexin system in the addictive properties of nicotine

Abstract

Hypocretin-1 and hypocretin-2, also known as orexin-A and orexin-B, are 2 neuropeptides that are exclusively expressed by a small subset of neurons of the lateral hypothalamic area. Despite their restricted expression pattern, hypocretin-containing axons project widely throughout the brain and exert their physiological functions acting on 2 G protein coupled receptors, hypocretin/orexin receptor-1 and hypocretin/orexin receptor-2. Initially, the hypocretin system was related to the regulation of sleep/wake cycles and feeding behavior. Nevertheless, a growing body of evidence has accumulated over the last decade indicating a role for these neuropeptides in drug addiction. In the present thesis, we have evaluated the involvement of hypocretin transmission in the addictive properties of nicotine, the main psychoactive component that sustains tobacco addiction, by using behavioral and biochemical approaches. Our results indicate that hypocretin peptides, mainly through their actions upon hypocretin receptor-1, influence the severity of nicotine withdrawal and modulate the relapse to nicotine-seeking after prolonged periods of abstinence. Given the importance of withdrawal and relapse on the pathophysiology of nicotine addiction, we propose hypocretin receptor-1 as a promising therapeutic target for the development of novel smoking cessation therapies.