The discovery of a possible link between narcolepsy and hypocretin/orexin was made in 1999 by two different groups, only one year after hypocretins were first discovered (23,24). Lin and colleagues (25) reported that the sleep disorder canine narcolepsy is caused by mutation in the hypocretin receptor 2 gene with a loss of ligand binding and subsequent intracellular transduction signal (25). Chemelli et al. (26) reported that according to behavioral and electroencephalographic criteria, hypocretin knockout mice exhibit a phenotype strikingly similar to that of human narcolepsy. Subsequent studies have led to the establishment of multiple rodent models with hypocretin ligand or receptor abnormalities (27-29). Of special interest is the mouse and rat ataxin-3 transgenic model, which causes loss of hypocretin cells (30,31).
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