Both Short- and Long-Acting D-1/D-2 Dopamine Agonists Induce Less Dyskinesia than L-DOPA in the MPTP-Lesioned Common Marmoset (Callithrix jacchus)

Abstract

The current concept of dyskinesia is that pulsatile stimulation of D-1 or D-2 receptors by L-DOPA or short-acting dopamine agonists is more likely to induce dyskinesia compared to long-acting drugs producing more continuous receptor stimulation. We now investigate the ability of two mixed D-1/D-2 agonists, namely pergolide (long-acting) and apomorphine (short-acting), to induce dyskinesia in drugnaı ¨ve MPTP-lesioned primates, compared to L-DOPA. Adult common marmosets (Callithrix jacchus) were lesioned with MPTP (2 mg/kg/day sc for 5 days) and subsequently treated with equieffective antiparkinsonian doses of L-DOPA, apomorphine, or pergolide for 28 days. L-DOPA, apomorphine, and pergolide reversed the MPTP-induced motor deficits to the same degree with no difference in peak response. L-DOPA and apomorphine had a rapid onset of action and short duration of effect producing a pulsatile motor response, while pergolide had a slow onset and long-lasting activity producing a continuous profile of motor stimulation. L-DOPA rapidly induced dyskinesia that increased markedly in severity and frequency over the course of the study, impairing normal motor activity by day 20. Dyskinesia in animals treated with pergolide or apomorphine increased steadily, reaching mild to moderate severity but remaining significantly less marked than that produced by L-DOPA. There was no difference in the intensity of dyskinesia produced by apomorphine and pergolide. These data suggest that factors other than duration of drug action may be important in the induction of dyskinesia but support the use of dopamine agonists in early Parkinson’s disease, as a means of delaying L-DOPA therapy and reducing the risk of developing dyskinesia.