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NMDA receptor regulation of levodopa-induced behavior and changes in striatal G protein-coupled receptor kinase 6 and ß-arrestin-1 expression in parkinsonian rats

Authors Wu N, Song L, Yang X, Yuan W, Liu Z

Received 12 December 2012

Accepted for publication 26 January 2013

Published 26 March 2013 Volume 2013:8 Pages 347—352


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Na Wu, Lu Song, Xinxin Yang, Weien Yuan, Zhenguo Liu

Department of Neurology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

Background: Parkinson’s disease is a neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra. The dopamine precursor, levodopa, remains the most effective and common treatment for this disorder. However, long-term administration of levodopa is known to induce characteristic dyskinesia, and molecular mechanisms underlying dyskinesia are poorly understood.
Methods: In this study, we investigated the effect of 6-hydroxydopamine lesions in dopaminergic neurons and chronic treatment with levodopa on expression of G protein-coupled receptor kinase 6 and ß-arrestin-1, two key regulators of G protein-coupled receptors, in the rat striatum.
Results: We found that a unilateral 6-hydroxydopamine lesion reduced expression of G protein-coupled receptor kinase 6 and ß-arrestin-1 protein in the lesioned striatum. Reduction of these two proteins persisted in 6-hydroxydopamine-lesioned rats on chronic levodopa treatment for 23 days. In addition, coadministration of the N-methyl-D-aspartate receptor antagonist, MK-801, and levodopa reversed the reduction of G protein-coupled receptor kinase 6 and ß-arrestin-1 in the striatum. MK-801 also attenuated levodopa-induced dyskinetic behavior.
Conclusion: These data indicate that G protein-coupled receptor kinase 6 and ß-arrestin-1 in striatal neurons are sensitive to dopamine depletion and are downregulated in rats with Parkinson’s disease and in levodopa-treated rats with the disease. This downregulation seems to require activation of N-methyl-D-aspartate glutamate receptors.

Keywords: dopamine, levodopa, levodopa-induced dyskinesias, G protein-coupled receptors, G protein-coupled receptor kinase dyskinesia

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