Chemical communication between neurons is a basic mechanism of normal activity within the brain. Deterioration in the process of inter-neuronal chemical coupling can produce devastating consequences. A prime example, and the focus of the present research plan, is the loss of the dopaminergic input to the striatum, with the insidious onset of the neurological deficits characteristic of Parkinson's disease. Recent investigation has documented multifaceted changes that occur as the disease progresses in: 1) dopamine release from the nigrostriatal afferent terminals, 2) recognition of the neurotransmitter by the receptors on the postsynaptic target cell, and 3) translation of the stimulus into a meaningful signal within the striatum. Previous work in this laboratory combining in vitro autoradiography for the D1 dopamine receptor with immunohistochemical characterization of cyclic AMP- containing striatal elements has determined that the close aggregation of this receptor subtype with the second messenger containing neurons is lost following dopamine denervation of the striatum. This change persists for long time periods. The present research plan will extend these results and determine if pharmacological supplementation of either the dopamine precursor L-DOPA, or specific D1 or D2 dopamine receptor agonists will re-establish this unique morphochemical receptor pattern in a rat model of Parkinson's disease. Alternatively, structural determinant may be an obligation participant in the return of the dopamine receptor clustering in the dopamine denervated rat caudate nucleus. This possibility will be tested by implantation of a fetal mesencephalic anlage, in the striatum ipsilateral to the dopaminergic deafferentation. It is necessary to examine the disposition of both dopamine receptor subtypes in our paradigms, as recent work has convincingly demonstrated a functional interaction between the two subtypes for full expression of postsynaptic dopaminergic effects. It is anticipated that the proposed investigations will provide insight into the mechanism of dopamine receptor recovery that occurs following supplemental drug regimes and/or transplantation in Parkinson's disease, as well as contribute to basic knowledge of the mechanism of action of the dopamine receptors of the basal ganglia.
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