This proposal is a request for a K01 Mentored Research Scientist Development Award. The candidate is a neuropsychiatrist who is experienced in neurochemistry and neuropharmacology. The candidate proposes to gain experience in clinical and basic neuropharmacology. His goal is to develop better pharmacological treatments for human narcolepsy. Human narcolepsy is a sleep disorder affecting 0.05-0.16% of the general population. The objective of this proposal is to dissect the neurochemical control of sleep in narcolepsy using a pharmacological approach and to apply this knowledge to improve the treatment for human narcolepsy. This will not only benefit narcoleptic patients but also provide critical information on the neurochemical mechanisms generating normal sleep. The research is greatly facilitated by the use of a unique animal model of narcolepsy in which the condition is transmitted as a fully penetrant autosomal recessive trait. In the past several years, the candidate has focused on the pharmacological control of canine cataplexy, a pathological manifestation of REM sleep atonia. The results indicate that this symptom, as REM sleep, is mainly controlled by cholinergic and monoaminergic systems. Several receptor subtypes that mediate this neuropharmacological control (muscarinic M2, adrenergic alpha-lb and alpha-2/D2(3)) have been identified. In this award period, the candidate will: (1) apply the knowledge that the adrenergic system is the most important monoaminergic system for the control of cataplexy obtained using the canine model to improve the treatment of human cataplexy, (2) test the hypothesis that the wake-promoting effects of amphetamine-like compounds are mediated via presynaptic stimulation of the dopaminergic transmission by attempting to correlate the in vivo effects on sleep and in vitro binding affinities for dopamine transporter site, in vitro potencies of dopamine uptake inhibition and in vivo effects on dopamine efflux of various wake-promoting compounds, and (3) determine the sites of action of wake-promoting compounds. This will involve local drug injection and in vivo microdialysis experiments. As preliminary results suggest the involvement of the mesolimbocortical dopaminergic system in narcolepsy, the candidate will principally focus on this anatomical system. Results from the canine model concerning excessive sleepiness could also apply to human narcoleptics at a later stage. With this Research Scientist Development Award, the candidate will contribute to the development or better pharmacological treatments of human narcolepsy while also furthering the candidate's career objective to be an independent scientist.
