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Neural mechanisms of Levodopa induced motor complications in Parkinson’s disease Bowden, Gregory Neil

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a loss of dopamine (DA) neurons. Motor fluctuations and dyskinesia are common complications that appear with long-term Levodopa (Ldopa) therapy. A rat model of unilateral Parkinsonism was formed using 6-OHDA and treatment with L-dopa was conducted to induce dyskinesia. The abnormal involuntary movement (AIM) rating scale was used for monitoring the time-action curve of the L-dopa response. Striatal DA levels were investigated using in vivo microdialysis. Post-mortem brain sections were taken for autoradiography and in situ hybridization histochemistry. The validation study (Chapter II) indicates that the AIM rating scale is reproducible across test days and within its four subscores. This offers a reliability that allows for an expanded analysis of the time action curve of dyskinetic movements. The chronic L-dopa treatment study (Chapter III) demonstrates that AIM magnitude (Emax) correlates negatively with latency to onset and decay time, but positively with rising time. We found that prodynorphin mRNA in the striatum has a significant negative correlation with decay time, and a positive correlation with Emax. This upregulation of prodynorphin mRNA, is also associated with L-dopainduced dyskinesia and may contribute to the development of motor fluctuations. The microdialysis experiments (Chapter IV) show that a DA surge response is necessary to cause L-dopa-induced AIM. The time concentration curve of extracellular DA shows a left shift in dyskinetic rats after chronic pulsatile treatment. Also, partially lesioned rats show a smaller increase in extracellular DA levels with greater increase in extracellular DOPAC levels after L-dopa injection, compared to those with severe striatal DA terminal loss. This suggests that the severity of DA terminal loss is a factor determining the level of "DA surge" in the striatum after L-dopa administration. Experimental observations from this project indicate that both severe DA terminal loss in the striatum and L-dopa treatment contribute to the development of "DA surge" in the striatum with a therapeutic dose of L-dopa, which is in turn responsible for the development of response fluctuations and dyskinesia in a rat model of Parkinson's disease.

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