Increased D1 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 D1 and D2 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 D1 and D2 dopamine receptors within the striatum of normal, parkinsonian, nondyskinetic levodopa-treated parkinsonian, and dyskinetic levodopa-treated parkinsonian animals. Whereas D1 receptor expression itself is not related to dyskinesia, D1 sensitivity per D1 receptor measured by D1 agonist-induced [35S]GTPγS 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 D1 receptor–mediated transmission at the level of the direct pathway. Ann Neurol 2004