The overall aim of these studies is to obtain further insight into the role of the basal ganglia in motor control and the pathophysiology of movement disorders. Key aspects of current models of both hypokinetic (parkinsonism) and hyperkinetic (drug induced dyskinesias) disorders will be studied in the primate MPTP model of parkinsonism. In a first set of experiments, we will test the hypothesis that the major parkinsonian signs (akinesia, bradykinesia, tremor, rigidity) result from increased activity in the internal segment of the globus pallidus (GPi), the major output structure of the basal ganglia. Motor behavior will be examined in normal and parkinsonian monkeys, before and after reversible or permanent inactivation of GPi with intracerebral injections with the GABAreceptor agonist muscimol or the neurotoxin ibotenic acid. To test the hypothesis that the increased GPi output in parkinsonian monkeys is the result of increased excitatory drive from the subthalamic nucleus (STN) on GPi, we will also study the long-term effects of STN lesions in such animals. Comparison of the effects of STN and GPi lesions will provide information about the relative effects of such lesions on different parkinsonian motor signs. In additional studies, two hypotheses regarding the effects of DAergic agonists on parkinsonian animals will be tested: 1) that dopamine receptor agonists reverse parkinsonian signs by normalizing GPi output and 2) that drug-induced dyskinesias in parkinsonian animals result from subnormal neural activity in GPi. To this end, we will directly record GPi activity in parkinsonian animals treated with dopaminergic agonists in the Presence and absence of dyskinesias. To explore which pathways are involved in the development of drug-induced dyskinesias, the dyskinesia producing capabilities of DA receptor agonists win also be studied in parkinsonian monkeys with and without GPi or STN lesions. In a final set of studies, we will test the cardinal parkinsonian signs result from dopamine deficiency in the putamen, by reversibly blocking dopaminergic transmission in different locations within the basal ganglia in normal monkeys with direct injections of haloperidol. In a companion study, dopamine receptor agonists will be injected in parkinsonian monkeys into various basal ganglia nuclei in order to determine the most effective site(s) of local dopaminergic repletion for the reversal of parkinsonian signs. Taken together, these studies will help to clarify the pathophysiologic basis of parkinsonian signs and drug-related dyskinesias, will directly test the therapeutic benefits of specific lesioning and drug-treatment strategies, and may lead to important new-treatment strategies.
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