The goal of this project is to determine how monoamines, acetylcholine and other neurotransmitters interact in the central nervous system to regulate cataplexy and sleepiness in narcolepsy. Pharmacological compounds are injected into specific brain areas while cataplexy and sleep patterns are recorded. Neurotransmitter release is also measured in the same areas during cataplexy (in vivo dialysis). In the past award period, we have found that cholinoceptive sites within the basal forebrain (BF) and the pontine reticular formation (PRF) are hypersensitive to muscarinic stimulation and that this process contributes to cataplexy. Acetylcholine release is also increased in both areas during spontaneous cataplexy demonstrating that cholinergic systems are active during this behavior. We now hypothesize that emotional stimulation results in acetylcholine release in the BF. Because of the hypersensitivity, we hypothesize that this induces widespread cholinergic activation and REM sleep-like symptoms. A second important finding is that dopaminergic D2/D3 autoreceptor stimulation in the ventral tegmental area (VTA) produced sleepiness and cataplexy in narcoleptic dogs. Since the VTA is a major site of descending projections from the BF, we hypothesize that interactions between the VTA and the BF contribute to the excessive daytime sleepiness experienced by narcolepsy. In the next award period, we will conclusively test these hypotheses using the same methodological approach. We will also further characterize the involvement of adrenergic systems as our results to date surprisingly suggest that the site of action of adrenergic compounds on cataplexy may not involve the locus coeruleus. Immunocytochemical techniques using cholera toxin and mapping studies of the cholinergic and monoaminergic neuronal systems will also be done to identify neuroanatomical connections. Using these approaches, we will establish a neurochemical and neuroanatomical map of the structures and neurotransmitters that control rapid eye movement (REM) sleep and produce the abnormal manifestations of narcolepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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Stanford University
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