Parkinson's disease (PD) affects about 1,000,000 people in North America. The symptoms of Bradykinesia/akinesia, tremor, rigidity and postural instability result from degeneration of nigrostriatal neurons and subsequent striatal dopamine deficiency. Initially, treatment with I- dopa, a precursor of dopamine, ameliorate the symptoms, but many patients develop serve involuntary movements (dyskinesias) from nearly every dose of I-dopa, thereby limiting effective treatment. It has been suggested that chronic I-dopa therapy causes changes in BG pathways leading to dyskinesias form individual doses of I-dopa. We propose to use several methods including position emission tomography (PET) and magnetic resonance imaging (MRI) to investigate the pathophysiologic mechanisms leading to the development of these involuntary movements. We hypothesize that chronic exposure to drugs produces alterations in basal ganglia (BG) pathways of parkinsonian subjects. In particular, we propose that such changes differentially affect the D1-mediated direct and D2-mediated indirect pathways that connect the striatum (input area of the BG) to the globus pallidus (output area of the BG). We also propose that the schedule of drug administration (either pulsatile or continuous) may affect both the development of dyskinesias and the changes induced in BG pathways. Monkeys made hemiparkinsonian by intracarotid (i.c.) infusion of MPTP will be used to study the effects of chronic treatment under tightly controlled conditions. Although the MPTP model is a reasonably faithful model of idiopathic PD, it is not the actual disease. Therefore, we will compare our findings in monkeys with a parallel study in patients with PD. BG pathways will be assessed by changes in regional cerebral blood flow (rCBF) induced by selective dopaminergic drug. We will perform additional studies to assess dopaminergic pathways in the BG of the hemiparkinsonian monkeys. PET methods will be used to assay dopaminergic receptor binding in vivo. In vitro measurements will include dopaminergic receptor binding, levels of expression of messenger RNAs (mRNAs) encoding for D1, D2 and D3 dopaminergic receptors, and levels of mRNA encoding for enkephalin, substance P and human findings should complement each other, improve our understanding of the mechanisms underlying development of drug-induced dyskinesias and subsequently provide an improved rationale for pharmacotherapy of PD.
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