Narcoleptic patients suffer from excessive daytime sleepiness, cataplexy, hypnagogic hallucinations and sleep attacks. Another identifying feature of narcolepsy is th entry into REM sleep directly from wakefulness. These symptoms are serious enough to disrupt the patients will being and may also be responsible for life threatening accidents. The disease appears to be a disorder of mechanisms controlling REM sleep because some narcoleptic symptoms, such as cataplexy and hypnagogic hallucinations are components of REM sleep, and in narcolepsy these components inexplicably encroach into the waking state. there is considerable evidence that acetylcholine plays an important role in triggering REM sleep, and the studies proposed in this grant application focus on delineating the cholinergic receptor subtype and neuronal elements related to this phase of sleep. The first experiment will serve to clarify the cholinergic receptor pharmacology involved in REM sleep generation. Pharmacological agents specific to the M1 and non-M1 receptors and nicotinic agents will be infused into the medial pontine reticular formation (mPRF), an area which has been shown to be important for REM sleep generation. The changes in REM sleep will be noted and comparisons between muscarinic and nicotinic mechanisms will be made. The second study will examine the glutaminergic pathway in the pons that along with the cholinergic pathway might represent the final common pathway involved in the atonia of REM sleep. Different retrograde tracers will be injected into the mPRF and the caudal medulla and the presence of the tracer will be examined in chemically identified glutaminergic somata in the dorsolateral pontine tegmentum. The third study will utilize fos-immunohistochemistry to reveal neuronal elements in the brainstem and forebrain related to REM sleep. The fos gene is triggered in response to neuronal stimulation and the presence of the protein allows for mapping of neuronal pathways. The protein might act as a third messenger serving to regulate the functional response of the cell. These studies will establish a groundwork for future work related to the transcriptional processes occuring during REM sleep.
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