Recent developments indicate that cell bodies in the caudate nucleus that synthesize prodynorphin peptides form a substantial projection to the substantia nigra. The presence of a projection system originating in the basal ganglia suggests that prodynorphin peptides might be involved in extrapyramidal motor function. The demonstration of motor effects after substantia nigra microinjections also supports a role of these peptides in the generation or patterning of movement. To determine the role of prodynorphin products in this pathway, we propose to carry out electrophysiological and behavioral studies in rats. In particular, we will identify the types of cells (output cells, dopamine cells, etc.) in the substantia nigra that are affected by iontophoretic application of the various products of prodynorphin. We will also use electrical stimulation combined with recording methods to determine the sites of action of the endogenously-released peptides. Additionally, we will conduct behavioral studies to verify the electrophysiology and to more directly observe the functional properties of this family of neurotransmitters in the subtantia nigra. The systems under investigation are of particular importance in the field of neurology. Pathology of the extrapyramidal motor system is a crucial factor in diseases such as Parkinson's disease and Huntington's chorea. The substantia nigram, a target of the proposed research, is of particular relevance in Parkinson's disease since marked pathology occurs in this nucleus. Therefore, a delineation of the actions of neurotransmitters active in this system might lead to rational therapies for a number of extrapyramidal disorders.
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