Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation

Neurons containing the neuropeptide orexin (hypocretin) are located exclusi vely in the lateral hypothalamus and send axons to numerous regions through out the central nervous system, including the major nuclei implicated in sl eep regulation, Here, we report that, by behavioral and electroencephalogra phic criteria, orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, as well as canarc-1 mutant dogs, the only kno wn monogenic model of narcolepsy. Moreover, modafinil, an anti-narcoleptic drug with ill-defined mechanisms of action, activates orexin-containing neu rons. We propose that orexin regulates sleep/wakefulness states, and that o rexin knockout mice are a model of human narcolepsy, a disorder characteriz ed primarily by rapid eye movement (REM) sleep dysregulation.