This is the first competitive continuation of an ongoing NIH application to investigate dopa-dyskinesias in parkinsonian MPTP-lesioned monkeys. The long-term goal of this work is to elucidate the mechanisms underlying this devastating complication of chronic L-dopa therapy, which is a major barrier for the successful treatment of Parkinson's disease. During the course of our ongoing grant, we unexpectedly observed that normal animals also developed dopa-dyskinesias, in contrast to previous work which suggested that a nigrostriatal deficit is essential for this complication of L-dopa therapy. This new non-lesioned model of dopa-dyskinesias may provide insight concerning the etiology of these movement abnormalities because it allows us to investigate this phenomenon in a setting that is not confounded by an already damaged nigrostriatal system. By examining the biochemical changes caused by L-dopa in unlesioned as compared to MPTP-lesioned animals, we should be able to identify common molecular mechanisms that underlie the development of typical dyskinesias. In this competitive continuation, the behavioral, cellular and molecular mechanisms associated with L-dopa-dyskinesias will be studied. This will be approached by (1) testing the hypothesis that a compromised nigrostriatal dopamine reuptake system predisposes to dopa-dyskinesias. This will be studied by initiating a drug-induced impairment of dopamine reuptake in normal animals to determine if there is an enhanced susceptibility to dopa-dyskinesias. (2) We will also investigate the relative roles of dopamine receptor subtypes (D1, D2 and D3) in the genesis of dopa-dyskinesias by administration of receptor subtype specific agonists and antagonists. (3) Our third specific aim will involve experiments to determine the integrity of the nigrostriatal system in the different groups of monkeys with dopa-dyskinesias. (4) Lastly, we will study the molecular events in the basal ganglia which mediate the development of dopa-dyskinesias using different models of dyskinesias described above. This will include alterations in dopamine receptor-linked coupling mechanism (such as dopamine-stimulated 35SGTPgammaS binding, DARPP-32 phosphorylation and adenylate cyclase activity), changes in NMDA receptor number and phosphorylation, and alterations in PPE mRNA levels. The results of this work will advance our understanding of the molecular mechanism responsible for the debilitating dyskinetic movements which occur as a consequence of long-term L-dopa treatment in Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034886-07
Application #
6711669
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Oliver, Eugene J
Project Start
1997-12-01
Project End
2006-08-31
Budget Start
2004-03-01
Budget End
2006-08-31
Support Year
7
Fiscal Year
2004
Total Cost
$380,252
Indirect Cost
Name
Parkinson's Institute
Department
Type
DUNS #
614259935
City
Sunnyvale
State
CA
Country
United States
Zip Code
94085
Quik, Maryka; O'Leary, Kathryn; Tanner, Caroline M (2008) Nicotine and Parkinson's disease: implications for therapy. Mov Disord 23:1641-52
Cox, Heather; Togasaki, Daniel M; Chen, Li et al. (2007) The selective kappa-opioid receptor agonist U50,488 reduces L-dopa-induced dyskinesias but worsens parkinsonism in MPTP-treated primates. Exp Neurol 205:101-7
Togasaki, Daniel M; Protell, Peter; Tan, Louis C S et al. (2005) Dyskinesias in normal squirrel monkeys induced by nomifensine and levodopa. Neuropharmacology 48:398-405
Togasaki, Daniel M; Hsu, Albert; Samant, Meghana et al. (2005) The Webcam system: a simple, automated, computer-based video system for quantitative measurement of movement in nonhuman primates. J Neurosci Methods 145:159-66
Chen, L; Togasaki, D M; Langston, J W et al. (2005) Enhanced striatal opioid receptor-mediated G-protein activation in L-DOPA-treated dyskinetic monkeys. Neuroscience 132:409-20
Hsu, Albert; Togasaki, Daniel M; Bezard, Erwan et al. (2004) Effect of the D3 dopamine receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on L-3,4-dihydroxyphenylalanine-induced dyskinesias and parkinsonism in squirrel monkeys. J Pharmacol Exp Ther 311:770-7
Quik, M; Police, S; Langston, J W et al. (2002) Increases in striatal preproenkephalin gene expression are associated with nigrostriatal damage but not L-DOPA-induced dyskinesias in the squirrel monkey. Neuroscience 113:213-20
Tan, Louis C; Protell, Peter H; Langston, J William et al. (2002) The hyperkinetic abnormal movements scale: a tool for measuring levodopa-induced abnormal movements in squirrel monkeys. Mov Disord 17:902-9
Togasaki, D M; Tan, L; Protell, P et al. (2001) Levodopa induces dyskinesias in normal squirrel monkeys. Ann Neurol 50:254-7
Petzinger, G M; Quik, M; Ivashina, E et al. (2001) Reliability and validity of a new global dyskinesia rating scale in the MPTP-lesioned non-human primate. Mov Disord 16:202-7

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