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) Eleni C. Maratos, Michael J. Jackson, Ronald K. B. Pearce, Carla Cannizzaro, and Peter Jenner Neurodegenenerative Disease Research Centre, Guy’s, King’s and St. Thomas’ School of Biomedical Sciences, King’s College London, London, SE1 1UL, United Kingdom Received February 26, 2002; accepted July 23, 2002 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 in- duce dyskinesia compared to long-acting drugs pro- ducing more continuous receptor stimulation. We now investigate the ability of two mixed D-1/D-2 ago- nists, namely pergolide (long-acting) and apomor- phine (short-acting), to induce dyskinesia in drug- naı ¨ve MPTP-lesioned primates, compared to L-DOPA. Adult common marmosets (Callithrix jac- chus) 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 re- sponse. 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 continu- ous profile of motor stimulation. L-DOPA rapidly in- duced dyskinesia that increased markedly in sever- ity and frequency over the course of the study, im- pairing normal motor activity by day 20. Dyskinesia in animals treated with pergolide or apomorphine increased steadily, reaching mild to moderate sever- ity 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. © 2002 Elsevier Science (USA) Key Words: dyskinesia; L-DOPA; pergolide; apomor- phine; MPTP; marmoset; Parkinson’s disease. INTRODUCTION L-DOPA (levodopa; L-3,4-dihydroxyphenylalanine), in combination with the peripheral decarboxylase in- hibitors carbidopa or benserazide, is the most com- monly used treatment for Parkinson’s disease (PD). However, chronic treatment with L-DOPA is associated with loss of drug efficacy and the onset of dyskinesia affecting approximately 40% of patients (1, 25, 26, 58, 62, 78). In contrast, the use of dopamine agonists as early monotherapy in newly diagnosed patients with PD produces a much lower incidence of motor compli- cations over a 5-year period, even when L-DOPA rescue is required (41, 53, 54, 75–77). L-DOPA also readily induces dyskinesia in nonhu- man primates with 1-methyl-4-phenyl-1,2,3,6-tetrahy- dropyridine (MPTP)-induced nigral degeneration and established motor deficits (4, 52, 68). Again, a differ- ence was apparent when the repeated administration of clinically utilized dopamine agonists, such as bro- mocriptine and ropinirole, was shown to induce less dyskinesia than L-DOPA. Subsequent studies showed that both D-1 and D-2 dopamine agonists could induce dyskinesia in otherwise drug-naı ¨ve MPTP-lesioned pri- mates but that there was a difference between drugs based on their duration of effect. Long-acting agonists, such as bromocriptine, ropinirole, and cabergoline, in- duced only mild dyskinesia (4, 29, 31, 33, 52, 67, 68), whereas short-acting agonists, such as (+)-PHNO and quinpirole, induced marked dyskinesia (4, 32, 34, 50, 79). Indeed, the intermittent and continuous adminis- tration of the same short acting D-2 agonist U-91356A resulted in different outcomes (5). Thus, repeated sub- cutaneous administration induced marked dyskine- sia while subcutaneous infusion using an osmotic minipump resulted in mild involuntary movements. In a similar study, intermittent administration of the D-1 agonist SKF 82958 induced dyskinesia whereas no dys- kinesia was seen following continuous administration. Experimental Neurology 179, 90 –102 (2003) doi:10.1006/exnr.2002.8055 90 0014-4886/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.