In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 27, No. 52 ( 2007-12-26), p. 14338-14348
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.4223-07.2007
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2007
detail.hit.zdb_id:
1475274-8
SSG:
12
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