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The Journal of Neuroscience, December 26, 2007, 27(52):14338-14348; doi:10.1523/JNEUROSCI.4223-07.2007
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Neurobiology of Disease
RGS9–2 Negatively Modulates L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Experimental Parkinson's Disease
Stephen J. Gold,1 Chau V. Hoang,1 Bryan W. Potts,1 Gregory Porras,2 Elsa Pioli,2 Ki Woo Kim,1 Agnes Nadjar,2 Chuan Qin,3 Gerald J. LaHoste,4 Qin Li,3 Bernard H. Bioulac,2 Jeffrey L. Waugh,1 Eugenia Gurevich,5 Rachael L. Neve,6 andErwan Bezard2,3 1Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, 2Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5227, Universite Victor Segalen-Bordeaux 2, 33076 Bordeaux, France, 3Institute of Lab Animal Sciences, Chinese Academy of Medical Sciences, 100021 Beijing, China, 4Department of Psychology, University of New Orleans, New Orleans, Louisiana 70148, 5Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, and 6Department of Genetics, Harvard Medical School, Belmont, Massachusetts 02478
Correspondence should be addressed to Erwan Bezard, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5227, Universite Bordeaux 2, 146 Rue Leo Saignat, Bordeaux 33076, France. Email: erwan.bezard{at}u-bordeaux2.fr
Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9–2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9–2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9–2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9–2 overexpression – achieved by viral vector injection into the striatum – diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9–2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the time course of viral vector-mediated striatal RGS9–2 overexpression parallels the time course of improvement of L-dopa-induced involuntary movements. We also find that unilateral 6-OHDA-lesioned RGS9–/– mice are more susceptible to L-dopa-induced involuntary movements than unilateral 6-OHDA-lesioned RGS9+/+ mice, albeit the rotational behavior – taken as an index of the anti-parkinsonian response – is similar between the two groups of mice. Together, these findings suggest that RGS9–2 plays a pivotal role in LID pathophysiology. However, the findings also suggest that increasing RGS9–2 expression and/or function in PD patients may only be a suitable therapeutic strategy to control involuntary movements induced by nonselective DA agonist such as L-dopa.
Key words: RGS proteins; dopamine receptor; Parkinson's disease; knock-out mouse; dyskinesia; monkey
Received March 26, 2007; accepted Nov. 11, 2007.
Correspondence should be addressed to Erwan Bezard, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5227, Universite Bordeaux 2, 146 Rue Leo Saignat, Bordeaux 33076, France. Email: erwan.bezard{at}u-bordeaux2.fr
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[Abstract] [Full Text] [PDF]
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