Increased D sub(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 sub(1) and D sub(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 sub(1) and D sub(2) dopamine receptors within the striatum of normal, parkinsonian, nondyskinetic levodopa-treated parkinsonian, and dyskinetic levodopa-treated parkinsonian animals. Whereas D sub(1) receptor expression itself is not related to dyskinesia, D sub(1) sensitivity per D sub(1) receptor measured by D sub(1) agonist-induced [ super(35)S]GTP gamma S 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 (DARPP-32). Our data suggest that levodopa- induced dyskinesia results from increased dopamine D sub(1) receptor-mediated transmission at the level of the direct pathway. Ann Neurol 2004