Parkinson's disease (PD) is a disabling basal ganglia disorder affecting 2% of the population over age 60. Four issues in the pathophysiology and pharmacotherapy of PD will be examined. 1) Striatal dopamine (DA) deficiency is the critical neurochemical correlate of PD; the motor signs of PD are due to altered descending physiologic input to the spinal cord. We propose to study regional cerebral glucose utilization (RCGU) by the 2-deoxyglucose (2-DG) autoradiographic method in rats with 6-hydroxydopamine (6- OHDA) substantia nigra (SN) lesion. Suprasegmental motor nuclei will be comprehensively examined to answer the question; Which CNS motor regions are functionally disturbed as a consequence of striatal DA deficiency? 2) To determine which CNS motor regions mediate the therapeutic response to dopaminergic drugs, we will study RCGU in suprasegmental motor nuclei following systemic drug treatment in rats with SN lesions. The functional role of D-1 and D2 DA receptors will be examined by studying the effects of selective D-1 and D2 agonists. 3) We will test the hypothesis that anticholinergic drugs achieve effect in PD by inhibiting the reuptake of DA into terminals, thereby functioning as indirect acting DA agonists. The RCGU effects of anticholinergic drugs will be measured in rats with SN lesion to determine which striatal outflow nuclei are functionally activated. The ability of anticholinergic drugs to alter striatal extracellular DA concentrations will be measured by in vivo brain dialysis. 4) Potential mechanisms of supersensitivity to DA agonists in PD will be examined. Drug delivery to the DA-depleted striatum will be assessed by measuring regional cerebral blood flow and in vivo extracellular DA levels afer Ldopa administration. Receptor mechanisms will be examined by determining the affinity (Kd) and capacity (Bmax) of D-1 and D-2 binding sites following SN lesion, as well as the fractional occupancy of each site after systemic drug adminstration. Results of these studies should facilitate the rational use of available agents and suggest new pharmacologic strategies for the treatment of PD.
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