BASAL GANGLIA--MOLECULAR PHARMACOLOGY AND ANATOMY

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Dopamine and acetylcholine have profound modulatory effects in the primate neostriatum. The receptors mediating these effects are important targets for drug therapies, as dysfunction of these transmitter systems is central to the pathogenesis of Parkinson's disease and other movement disorders. Recently, a large and diverse group of genetically distinct receptor subtypes have been identified. Although their distributions and functions are largely unknown, D1 and D2 (dopamine) and m1, m2 and m4 (muscarinic acetylcholine) are the major receptor subtypes present in the putamen. We have recently developed immunological methods for localization of these dopamine and muscarinic acetylcholine receptors using antibodies to be subtype-specific by immunoblotting and immunoprecipitation of the cloned and native receptors. Preliminary immunocytochemical findings in rat, monkey, and human brain support our hypothesis that individual motor putamen. The first goal of these studies is to delineate the regional and cellular distributions D1, D2, m1, m2, and m4 receptors in monkey and human putamen by light microscopy, and their precise subcellular (e.g., pre- and postsynaptic) distributions in monkeys putamen by electron microscopy. In addition, D1 will be co- localized with the other receptors to determine if the subtypes are expressed in the same, overlapping, or segregated populations of neurons in putamen. The second goal is to determine the relationships of these receptors to putamenal neurons projecting to GPe and GPi, using combined retrograde tracing techniques and receptor immunocytochemistry. These studies will provide direct morphological evidence to support or refute models of receptor subtype segregation between parallel striatal output pathways. The third goal is to determine the synaptic relationships of the receptors wit identified putamental afferent. Afferent from primary and supplementary motor cortices, motor thalamus (centromedian nucleus), substantia nigra, and the midbrain tegmental extrapyramidal area will be identified by anterograde tracing at light and electron microscopic levels. The results will advance our understanding of the molecular pharmacology and synaptic organization of the primate basal ganglia, and will aid in the rational development of more specific and effective drugs, aimed at these molecular targets, for the treatment of Parkinson's disease and other disorders of the basal ganglia.