Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function

In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), expression of the dopamine D 3 receptor was decreased. However, levodopa-induced dyskinesia (LID), similar to the debilitating and pharmacoresistant involuntary movements elicited after long-term treatment with levodopa in patients with Parkinson disease (PD), was associated with overexpression of this receptor. Administration of a D-3 receptor-selective partial agonist strongly attenuated levodopa-induced dyskinesia, but left unaffected the therapeutic effect of levodopa. In contrast, attenuation of dyskinesia by D-3 receptor antagonists was accompanied by the reappearance of PD-like symptoms. These results indicated that the D-3 receptor participated in both dyskinesia and the therapeutic action of levodopa, and that partial agonists may normalize D-3 receptor function and correct side effects of levodopa therapy in patients with PD.