Sub-chronic administration of the dopamine D1 antagonist SKF 83959 in bilaterally MPTP-treated rhesus monkeys:: stable therapeutic effects and wearing-off dyskinesia

Rationale: SKF 83959 acts as a D-1 antagonist in vitro but has been claimed to induce anti-parkinsonian effects after acute administration in MPTP-treated marmosets. Objective: The aim of the present study was to evaluate the therapeutic and undesired effects of subchronic administration of SKF 83959 in bilaterally MPTP-treated rhesus monkeys and to compare these effects with the effects of L-dopa and the dopamine agonist SKF 82958. Methods: MPTP was given in the left carotid artery (2.5 mg) and 6 weeks later, the right carotid artery (1.25 mg). The monkeys (n=4) had previously been treated chronically with L-dopa (22 days, 10 mg/kg) and SKF 82958 (22 days, 1 mg/kg). Three months after the last administration of SKF 82958, SKF 83959 was given in a dose of 0.5 mg/kg: from day 1 to day 15 and in a dose of 1.0 mg/kg from day 16 to day 18, Results:SKF 83959 increased goal-directed limb movements in all animals, including those unresponsive to L-dopa. This therapeutic effect did not diminish during treatment. With respect to body displacement and undesired effects, a large variation in the response to SKF 83959 was found: a large increase in body displacement co-occurred with oro-facial dyskinesia (n=2), whereas a small increase in body displacement co-occurred with dystonia (n=2). In contrast to the undesired effects of L-dopa, the dyskinetic effects of SKF 83959 were primarily limited to the first treatment day. Unlike L-dopa and SKF 82958, SKF 83959 did not induce epileptoid behaviour. Conclusion: Sub-chronic administration of SKF 83959 induced both clear-cut therapeutic effects that remained stable in time, and a limited number of dyskinetic effects that wore off during the treatment. The dopamine D-1 antagonist SKF 83959 may be considered as an alternative treatment in Parkinson's disease, especially in those patients who do not respond to L-dopa.