Central cholinergic systems are widely acknowledged to play a critical role in the generation of rapid eye movement (REM) sleep. The long term objectives of this proposal are to characterize the specific muscarinic and nicotinic cholinergic receptor mechanisms that generate REM sleep. This proposal further aims to extend the foregoing cholinergic hypothesis by examining the role of central cholinergic receptors in the generation of non-REM (NREM) sleep. Although it has been 25 years since the demonstration that central administration of acetylcholine produces both NREM and REM sleep, the precise receptor mechanisms that mediate the cholinoceptive evocation of sleep states have not been specified. Therefore, the proposed studies will characterize these receptor mechanisms by the following specific aims: (1) The hypothesis that muscarinic cholinergic receptors on pontine reticular formation neurons play a critical role in the generation of REM sleep will be tested by administering a range of dosages of cholinergic agonists and antagonists and determining their order of potency in enhancing or suppressing REM sleep (2) The hypothesis that nicotinic cholinergic receptors are also involved in REM sleep generation will be tested by administering nicotinic agonists and antagonists and quantifying the effects on REM sleep. (3) The hypothesis that cholinergic mechanisms of the basal forebrain are important in the generation of NREM sleep will be examined by administering cholinergic agonists and antagonists to the basal forebrain and quantifying the effects on NREM sleep. (4) As a first step toward testing the hypothesis that changes in muscarinic cholinergic receptor binding may be involved in regulating the sleep cycle, additional studies will localize, quantify, and characterize the binding properties of muscarinic, cholinergic receptors throughout the intact cat brain. These four specific aims will be achieved using the techniques of central microinjection to deliver cholinergic agonists and antagonists to specific brain stem and forebrain sites, and quantitative in vitro receptor autoradiography to map the distribution of muscarinic cholinergic receptors in the cat brain. Common neurobiological mechanisms have been suggested to underlie sleep cycle generation and the control of affective states. Thus, the health relatedness of the proposed research is the ability to further define, at the receptor level, neural systems controlling sleep and certain affective disorders.
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