Animal models of narcolepsy: Development, findings and perspectives

Two of the primary symptoms of narcolepsy, cataplexy and sleep attacks, have been amenable to study in canine and rodent models of narcolepsy. The canine model has proved to be an important research tool in the pathophysiology since the disorder was first identified in this species in 1973. Neurotransmitter differences in the narcoleptic canines, combined with evaluation of compounds that can both decrease and increase the incidence of cataplectic episodes, have provided insight into possible brain changes associated with the disorder, and suggested new treatment regimes. Since canine narcolepsy was found to be transmissible in at least two breeds, this model also provided a feasible tool for a genetic study of the disorder. A decade-long positional cloning effort eventually resulted in the identification of the gene that was mutated in dogs: a receptor for the orexin (also called hypocretin) neuropeptides. Coincidentally, but independently, a mouse line was created with the orexin gene deleted. In a remarkable concordance of results, the discovery of both the canine gene and the narcoleptic phenotype of the orexin knockout mouse occurred within weeks, if not days, of each other. These studies resulted in an unequivocal linkage between the pathophysiology in the orexin system and the narcolepsy symptoms. Studies on these models are continued to understand how orexin might normally prevent the dysregulated transitions between different vigilance states, which appear to be at the core of the narcoleptic symptomatology. The etiology of the disorder, and the nature and mechanism of cataplexy remain important issues that are amenable to research with the animal models.