Orexin/Hypocretin, Drug Addiction, and Narcolepsy

The hypothalamic neuropeptide orexin (hypocretin) influences a range of behaviors ranging from feeding to sleep and arousal. While genetic studies in rodents first demonstrated a role of orexin in narcolepsy with cataplexy, more recent work has brought attention to the role of orexin in drug addiction. Orexin influences many aspects of drug addiction, including drug dependence, reward, and reinstatement. Data suggest that orexin acts through its receptors to influence the mesocorticolimbic ­dopamine pathways that are known to underlie responses to drugs of abuse and the development of addiction. Importantly, orexin may also influence positive and negative (stress) states that can in turn influence addiction. The orexin neurons project broadly and the receptors are widely expressed, making it challenging to determine the circuits that are central to these effects. It may be that overlapping or ­distinct circuits are mediating orexin’s influence on reward/addiction or arousal/narcolepsy.