Acetylcholine is well established as a neurotransmitter in the mammalian CNS, mediating a wide variety of responses mainly via activation of muscarinic receptors. The muscarinic system is functionally very important since, in addition to regulating normal neuronal excitability, it is implicated in a number of disease states, including Alzheimer's, Parkinson's and epilepsy, and modulation of long-term potentiation, a candidate mechanism of memory and learning. Recent pharmacological and molecular biological work has revealed a diversity of muscarinic receptor subtypes and associated second messenger systems. The central hypothesis of this proposal is that different muscarinic receptor subtypes mediate different responses.
The specific aims of this proposal are to: 1) determine if the subtypes in hippocampus correspond to established subtypes as defined by pharmacological techniques, 2) identify the functional roles of the various subtypes, and 3) investigate the possible involvement of second messengers in muscarinic responses associated with specific subtypes. Several electrophysiological responses to muscarinic agonists will be studied using intracellular techniques (current-clamp and single-electrode voltage-clamp) in the rat hippocampal slice, including: Muscarinic depolarization, block of several ionic conductances and inhibition of G-protein-related transmitter responses. The heterogeneity of muscarinic receptors will be determined quantitatively by Schild plot analysis of the effects of competitive antagonists. The role of second messenger systems in muscarinic responses will be investigated by a pharmacological approach to mimic, inhibit or augment the actions of the systems activated by muscarinic agonists. Deficits in cholinergic systems, including the possible selective loss of particular receptor subtypes, occurs in Alzheimer's and Parkinson's diseases. A better understanding of the function of the muscarinic receptor subtypes could contribute to the rational design of drug therapy for several disease states.
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