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Hypocretin/Orexin: A Molecular Link Between Sleep, Energy Regulation, and Pleasure

Received January 10, 2006; revised February 1, 2007; accepted February 1, 2007. Dr. Ganjavi is affiliated with the Faculty of Medicine, University of Toronto, Canada. Dr. Shapiro is affiliated with the Sleep and Alertness Clinic, University Health Network, University of Toronto, Toronto Western Hospital, Canada. Address correspondence to Dr. Shapiro Toronto Western Hospital, 399 Bathurst Street, 7 Main-421 Toronto M5T 2S8, Canada; colin.shapiro{at}uhn.on.ca (e-mail).

Hypocretin (Hcrt) is a neurotransmitter of the dorsal and lateral hypothalamus that regulates sleep, appetite, and energy consumption. Recent evidence indicates that it is also involved in pleasure/reward-seeking. Mutation of the Hcrt-receptor gene causes narcolepsy in canines, and Hcrt knockout mice exhibit narcolepsy-like symptoms. Human narcoleptics do not commonly have mutations in the ligand or receptor but do have degeneration of Hcrt-containing neurons, possibly through an autoimmune mechanism. When Hcrt neurons degenerate in mice, hypophagia and obesity are observed, symptoms that are also present in some human narcoleptics. This article reviews the recent literature with regard to the many functions of this single molecule. The authors suggest that eating habits and impulsivity may be topics worth exploring in the evaluation of narcoleptic patients.

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