Loss of dopaminergic innervation of the striatum in Parkinson's disease (PD) results in overactivity of the glutamatergic pathways from the subthalamic nucleus to the internal segment of the globus pallidus and the substantia nigra par's reticulate, the output nuclei of the basal ganglia. Previous work has shown that local blockade of glutamate receptors in the internal'segment of globus pallidus or substantia nigra pars reticulate leads to marked suppression of parkinsonian signs. Our laboratory has shown that systemic administration of glutamate antagonists has profound antiparkinsonian effects, without apparent side effects, in rodent and primate models of PD. In addition, we have provided evidence of regulatory changes in glutamate receptors and mitochondrial enzyme activity in a rodent model of PD. We now propose to study in a systematic fashion the effects of various classes of glutamate antagonists in a primate model of PD, and to examine functional changes the glutarraterc system in rodent and primate models of PD. We will: (1) Examine the antiparkinsonian effects of glutamate antagonists of various classes (alone and in combination with levodopa) in a stable, bilateral monkey model of parkinsonism. (2)-Determine whether those glutamate antagonists showing antiparkinsonian effects and synergy with levodopa synergize both with selective DI and selective D2 agonists. (3) Determine whether the combined antiparkinsonian effects of an NMDA and AMPA antagonist are additive, synergistic, or neither. (4) Determine whether concurrent treatment with NMDA receptor antagonists can prevent or delay the onset of levodopa-induced dysl:inesias in monkeys with """"""""de novo"""""""" parkinsonism. (5) Use quantitative receptor autoradiography, it! Sitll hybridization and immunocytochemistry to map alterations in glutamate receptors in rats and monkeys with unilateral lesions of the nigrostriatal doparrane system. (6) Map changes in NADH:ubiquinone oxidoreductase (complex I), succinate dehydrogenase (complex II) and cytochrome oxidase (complex IV) in rats and monkeys with unilateral lesions of the nigrostriatal doparrane system. By using techniques ranging from measurement of receptor subumit message to preclinical testing of drugs in p~insotuan monkeys, we plan to take a comprehensive approachto the study of glutamate iff Parkinson's disease. It is anticipated that our studies will result in an improved understanding of the pathophysiology of this disorder and lead directly to improved therapies.
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