Inhibition of striatal dopamine D receptor attenuates levodopa-induced dyskinesia in a rat model of Parkinson's disease.

Levodopa-induced dyskinesia (LID) is experienced by most patients of Parkinson's disease (PD) upon the long-term use of the dopamine precursor levodopa. Striatal dopaminergic signaling plays a critical role in the pathogenesis of LID through its interactions with dopamine receptors. The specific roles of striatal dopaminergic D receptors in the pathophysiological process of LID are still poorly established. In the study, we investigated the role of striatal dopamine D receptor in LID by using PD rats with or without dyskinetic symptoms after chronic levodopa administration. The experimental results showed that the expression level of D receptors in the sensorimotor striatum of dyskinetic rats is significantly higher than that of the non-dyskinetic controls. The administration of levodopa increased c-Fos expression in a subpopulation of sensorimotor striatum neurons of dyskinetic rats, but not in non-dyskinetic rats. The majority of the c-Fos neurons activated by levodopa in the striatum are positive for D receptor staining. Intrastriatal injection of D-like (D and D) dopamine receptor antagonist, SCH-23390, significantly inhibited dyskinetic behavior in dyskinetic rats after the injection of levodopa, meanwhile, intrastriatal administration of SKF-83959, a partial D receptor agonist, yielded significant dyskinetic movements in dyskinetic rats without levodopa. In contrast, intrastriatal perfusion of small interfering RNA directed against DRD5 downregulated D receptors expression and moderately inhibited dyskinetic behavior of dyskinetic animals. Our data suggested that the striatal dopamine D receptor might play a novel role in the pathophysiology of LID.