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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033779-08
Application #
6393700
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Sheehy, Paul A
Project Start
1995-01-01
Project End
2004-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
8
Fiscal Year
2001
Total Cost
$420,892
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Betarbet, Ranjita; Poisik, Olga; Sherer, Todd B et al. (2004) Differential expression and ser897 phosphorylation of striatal N-methyl-d-aspartate receptor subunit NR1 in animal models of Parkinson's disease. Exp Neurol 187:76-85
Betarbet, Ranjita; Greenamyre, J Timothy (2004) Regulation of dopamine receptor and neuropeptide expression in the basal ganglia of monkeys treated with MPTP. Exp Neurol 189:393-403
Betarbet, Ranjita; Sherer, Todd B; Greenamyre, J Timothy (2002) Animal models of Parkinson's disease. Bioessays 24:308-18
Sherer, Todd B; Betarbet, Ranjita; Greenamyre, J Timothy (2002) Environment, mitochondria, and Parkinson's disease. Neuroscientist 8:192-7
Blandini, F; Nappi, G; Greenamyre, J T (2001) Subthalamic infusion of an NMDA antagonist prevents basal ganglia metabolic changes and nigral degeneration in a rodent model of Parkinson's disease. Ann Neurol 49:525-9
Greenamyre, J T (2001) Glutamatergic influences on the basal ganglia. Clin Neuropharmacol 24:65-70
Greenamyre, J T; Sherer, T B; Betarbet, R et al. (2001) Complex I and Parkinson's disease. IUBMB Life 52:135-41
Pettus, E H; Betarbet, R; Cottrell, B et al. (2000) Immunocytochemical characterization of the mitochondrially encoded ND1 subunit of complex I (NADH : ubiquinone oxidoreductase) in rat brain. J Neurochem 75:383-92
Betarbet, R; Porter, R H; Greenamyre, J T (2000) GluR1 glutamate receptor subunit is regulated differentially in the primate basal ganglia following nigrostriatal dopamine denervation. J Neurochem 74:1166-74
Talpade, D J; Greene, J G; Higgins Jr, D S et al. (2000) In vivo labeling of mitochondrial complex I (NADH:ubiquinone oxidoreductase) in rat brain using [(3)H]dihydrorotenone. J Neurochem 75:2611-21

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