A pharmacological approach will be used to study the neurochemical control of cataplexy and excessive daytime sleepiness in narcolepsy. In previous funding periods, the investigator has studied the pharmacological control of cataplexy using a canine model of narcolepsy; the effects of more than 200 investigational compounds with established pharmacological profiles have been evaluated, thus providing a basis for further neuroanatomical studies in the disorder. In this competitive renewal, the investigator will now use knowledge gathered from narcoleptic canines to improve anti- cataplectic treatments in humans. The mode of action of wake-promoting compounds (e.g., amphetamine-like stimulants) will also be studied using the canine model of the disorder. Gaining more knowledge of the mode of action of wake-promoting compounds is relevant not only for narcoleptic patients but also for all other patients with disorders associated with daytime sleepiness, and for the field of drug abuse. A third emphasis of this proposal will be to study the effects of immuno-modulators in narcolepsy; this area of investigation grew from the investigator's finding that thalidomide, a sedative-hypnotic with immunomodulatory effects, dramatically exacerbates canine narcolepsy in vivo. This last avenue of research might lead us to discover novel therapeutic approaches for human narcolepsy.
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