Inhibition of striatal dopamine D5 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 D5 receptors in the pathophysiological process of LID are still poorly established. In the study, we investigated the role of striatal dopamine D5 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 D5 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 D5 receptor staining. Intrastriatal injection of D1-like (D1 and D5) 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 D5 receptor agonist, yielded significant dyskinetic movements in dyskinetic rats without levodopa. In contrast, intrastriatal perfusion of small interfering RNA directed against DRD5 downregulated D5 receptors expression and moderately inhibited dyskinetic behavior of dyskinetic animals. Our data suggested that the striatal dopamine D5 receptor might play a novel role in the pathophysiology of LID.