Increased D-1 dopamine receptor signaling in levodopa-induced dyskinesia

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa therapy for Parkinson's disease. Although changes affecting D-1 and D-2 dopamine receptors have been studied in association with this condition.. no causal relationship has yet been established. Taking advantage of a monkey brain bank constituted to study levodopa-induced dyskinesia, we report changes affecting D-1 and D-2 dopamine receptors within the striatum of normal.. parkinsonian, nondyskinetic levodopa-treated parkinsonian, and dyskinetic levodopa-treated parkinsonian animals. Whereas D-1 receptor expression itself is not related to dyskinesia, D-1 sensitivity per D-1 receptor measured by D-1 agonist-induced [S-35]GTPgammaS binding is linearly related to dyskinesia. Moreover, the striata of dyskinetic animals show higher levels of cyclin-dependent kinase 5 (Cdk5) and of the dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARP-32). Our data suggest that levodopa-induced dyskinesia results from increased dopamine D-1 receptor-mediated transmission at the level of the direct pathway.