Loss of striatal dopaminergic innervation in Parkinson's disease (PD) is associated with complex changes in the functional and neurochemical anatomy of the basal ganglia. Prominent among the neurotransmitters; altered in PD is the glutamatergic system. For example, the glutamatergic pathways from subthalamic nucleus to the internal segment of globus pallidus and the substantia nigra pars reticulata become overactive after nigrostriatal dopamine depletion. Moreover, there is increasing evidence that corticostriatal projections also become overactive in models of PD. Our laboratory and others have shown that this glutamatergic overactivity has clinically relevant functional consequences and contributes importantly to the pathophysiology of parkinsonian signs and symptoms. Stereotactic or systemic blockade of glutamate receptors has remarkable antiparkinsonian and antidyskinetic effects in experimental animals and in patients with PD. We propose to continue to study in a systematic fashion the effects of various classes of glutamate antagonists in MPTP-treated parkinsonian monkeys, and to examine functional changes in the glutamatergic system in this model of PD. In so doing, we expect to identify viable pharmacological targets for therapeutic intervention in PD. Specifically we propose to: 1. Continue to examine the antiparkinsonian efficacy of a wide range of glutamate antagonists in MPTP-treated parkinsonian monkeys 2. Use various combinations of glutamate antagonists, individually demonstrated in Specific Aim 1 to be efficacious, and test for additive or synergistic actions. 3. Compare the development and severity of dyskinesias in de novo parkinsonian monkeys treated chronically with (1) levodopa alone, or (2) a combination of levodopa and an NMDA antagonist. 4. Examine the antidyskinetic efficacy of NMDA and AMPA receptor antagonists and glutamate release inhibitors in monkeys with established levodopa-induced dyskinesias. 5. Use immunocytochemistry and immunoautoradiography to map changes in basal ganglia glutamate receptors in MPTP-treated monkeys, and to use in vivo [3CH]dihydrorotenone binding to map metabolic changes in these brains. By using techniques ranging from measurement of receptor subunit protein levels to preclinical testing of drugs in parkinsonian monkeys, we plan to take a comprehensive approach to the study of glutamate in 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.
Showing the most recent 10 out of 22 publications
