The MPTP-treated primate as a model of motor complications in PD

Abstract

Motor complications are a common cause of treatment failure in Parkinson’s disease (PD). Although the underlying mechanisms remain obscure, research with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates may facilitate their investigation. Repeated administration of l-dopa to MPTP-treated primates results in a loss of drug efficacy (“wearing off”) and periods of immobility (“on-off”). Immediately after each dose of l-dopa, animals show an initial worsening of motor performance (“beginning-of-dose deterioration”) and, at the end of action of each dose, they exhibit a decline to levels of disability below those seen at baseline (“rebound worsening”). Dyskinesia (chorea, dystonia, athetosis) appears rapidly in MPTP-treated primates given l-dopa. The greater the degree of nigral denervation, the less exposure to l-dopa that is required to induce dyskinesia. The onset and intensity of dyskinesia are related to the dose and frequency of l-dopa administration. Increasing brain exposure to l-dopa increases the severity and intensity of involuntary movements. In contrast, long-acting dopamine agonists (DAs) induce a far lower incidence of dyskinesia, and continuous dopaminergic stimulation may provide a means of avoiding its onset. Recent data from MPTP-treated primates suggest that switching from l-dopa to a long-acting DA may reverse the priming process associated with induction of dyskinesia. Responses of MPTP-treated primates have proved to be highly predictive of antiparkinsonian activities of drugs in humans and their ability to induce dyskinesia, but they may also have utility in evaluating the mechanisms that underlie a range of long-term motor complications affecting patients with PD.