The proposal focuses on the role of muscarinic receptor subtypes, as defined by ligand specificity and selectivity for second messenger systems, in the regulation of cholinergic systems. The effects of acute and long-term administration of muscarinic agents will be examined through autoradiographic measures of receptor binding and by monitoring behavioral changes associated with receptor adaption. Experiments are designed to determine the relative contribution of M1 and M2 receptors to receptor upregulation and downregulation respectively. This will be accomplished by measuring the effects of exposures to pirenzepine, gallamine and AFDX-116 on the number and affinity of muscarinic receptors through autoradiographic methods. Downregulation of muscarinic receptors by increased levels of acetylcholine is expected to develop following long-term exposure to presynaptic antagonists such as gallamine, while pirenzepine will cause upregulation. The regulation of muscarinic receptors by acetylcholine is an important consideration for long-term treatment of cholinergic disorders. Recent advances in the treatment of Alzheimer's disease focus on the use of cholinesterase inhibitors to elevate levels of acetylcholine. In this regard, it is necessary to determine if selective or partial agonists also induce a decrease in muscarinic receptors. The development of agents which activate muscarinic receptors without inducing receptor downregulation may provide effective, prolonged treatment for Alzheimer's patients. The effects of partial agonists on performance of a behavioral task dependent on memory will provide an in vivo measure of cholinergic activity. The selectivity of partial agonists for muscarinic receptor second messenger systems provides a rational approach for activation of the muscarinic receptors important for memory function, without interfering with receptor involved in receptor down-regulation or desensitization. Taken together, the experiments will determine the role of muscarinic receptor subtypes in the regulation of receptor number. Regulation will be measured first by the use of selective antagonists and then by selective agonists. The results from both neurochemical and behavioral assays will provide important information relating muscarinic receptor regulation to behavior adaptation.
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