Induction by dopamine D₁ receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease

Background: Dyskinesias are a frequent adverse effect of long-term levodopa therapy. The relative contribution of dopamine D₁ and D₂ receptor function to the pathophysiology of levodopa-induced dyskinesias remains a matter of controversy. Objective: To establish whether a selective D_t dopamine agonist induces more or less dyskinesia than levodopa in primed dyskinetic patients with Parkinson disease. Methods: We studied ABT-431, the prodrug of a fully selective D_t agonist, in 20 subjects with advanced Parkinson disease and a fluctuating response to levodopa complicated by dyskinesias. Eight patients were studied in a double-blind, randomized design (French centers); 12, in an open, randomized design (US centers). We assessed and compared the antiparkinsonian (Unified Parkinson's Disease Rating Scale) and dyskinetic (response induced by an acute challenge of a suprathreshold dose of levodopa and by 4 different ascending doses (5, 10, 20, and 40 mg) of ABT-431 during the 6 hours after the challenge. Results: The separate analysis of the double-blind and open data led to the same findings, ie, the antiparkinsonian and dyskinetic responses induced by ABT-431 were dose related. At the most effective doses (20 and 40 mg), ABT-431 exhibited similar antiparkinsonian benefit and produced similar dyskinesias as levodopa. Conclusion: Dopamine D_t agonists can induce a full antiparkinsonian response but do not support previous hypotheses suggesting that D_t agonists are more or less likely to produce dyskinesias than levodopa.