RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson's disease

J Neurosci. 2007 Dec 26;27(52):14338-48. doi: 10.1523/JNEUROSCI.4223-07.2007.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Corpus Striatum / metabolism
  • Corpus Striatum / physiopathology
  • Dihydroxyphenylalanine / adverse effects*
  • Disease Models, Animal
  • Dopamine Agents / adverse effects*
  • Dyskinesias / etiology*
  • Dyskinesias / physiopathology*
  • Dyskinesias / therapy
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • MPTP Poisoning / drug therapy
  • Macaca fascicularis
  • Mice
  • Mice, Knockout
  • Oxidopamine / pharmacology
  • RGS Proteins / administration & dosage
  • RGS Proteins / metabolism*
  • Stereotyped Behavior / drug effects
  • Stereotyped Behavior / physiology*
  • Sympatholytics / pharmacology


  • Dopamine Agents
  • RGS Proteins
  • Sympatholytics
  • regulator of g-protein signaling 9
  • Dihydroxyphenylalanine
  • Oxidopamine