The long-term goal of this work is to elucidate the mechanisms underlying the dyskinesias which develop in Parkinson's disease in response to chronic L-dopa treatment, and to identify therapeutic means to ameliorate or prevent them. The pathogenesis of L-dopa-induced dyskinesias remains poorly understood; however, since a combination of striatal dopaminergic denervation and chronic drug administration are both required for its induction, it is generally thought that a complex series of changes in basal ganglia circuitry is involved. In this proposal, we will test specific alterations in both pre- and postsynaptic neuronal function in distinct regions of the basal ganglia thought to be involved in dopa-dyskinesias and correlate observed changes with the onset and/or occurrence of dyskinesias. To approach this we will test the hypotheses (1) that, with a decline in the number of surviving dopaminergic neurons, there is a decreased capacity to buffer changes in the availability of L-dopa and/or dopamine, (2) that specific dopamine receptor subtype modifications in the striatopallidal complex and other brain areas are linked to the onset of L-dopa-induced dyskinesias and (3) that glutamate receptors are upregulated with the occurrence of dyskinesia as studies have shown that glutamate receptor blockers suppress dyskinesias. We will use a well-characterized model, developed in our laboratory, of dopa-dyskinesias in squirrel monkeys rendered parkinsonian by systemic injection of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since the observed dyskinesias are essentially identical to those which occur in parkinsonian patients and in humans with MPTP-induced parkinsonism, we have an excellent experimental paradigm with which to investigate the current hypotheses on the pathophysiology of dopa-dyskinesias. These studies will enhance our understanding of the pathophysiology of dopa-dyskinesias, and could lead to new strategies for their prevention.
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