The proposed work is based on a multidisciplinary approach to the study of the central nervous system with particular emphasis on the application of biochemical and histological techniques to better understand the role of neurotransmitter systems in mediating behavioral function. A variety of techniques are ongoing in the laboratory to examine the involvement of muscarinic cholinergic systems in behavior. Autoradiographic studies have identified regions of brain with unique populations of muscarinic receptor subtypes. Assays of muscarinic receptor activity, including phosphoinositide turnover, GTP hydrolysis and regulation of acetylcholine release, have increased our understanding of the consequences of the action of subtype-selective muscarinic drugs. Behavioral testing using selective muscarinic antagonists and cholinergic neurotoxins has contributed to our understanding of the types of muscarinic receptors involved in memory function as well as the physiological consequences of long-term administrations of muscarinic agents. Recent work in the laboratory has focused on the development of novel muscarinic agonists for treatment of Alzhemier's disease. The proposed studies will extend our understanding of the role of muscarinic systems in behavior and provide new information necessary for rational approaches to the treatment of neurological disorders. Specifically, receptor binding studies utilizing selective muscarinic ligands will be extended, using cloned muscarinic receptors as expressed in A9 L cells. In addition, the techniques of immunocytochemistry and in situ hybridization will be applied to better understand the neuroanatomical sites of action of selective muscarinic drugs and their relationship with other neurotransmitter systems. The long-term objective is a better understanding of how neurotransmitters and drugs, working at the molecular level, mediate specific behavioral responses. The proposed studies will increase our knowledge of disease processes, and provide rational approaches for therapeutic intervention in a variety of disorders including Alzheimer's disease, Parkinson's disease, anxiety, strokes, and drug abuse.
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