Sustained cabergoline treatment reverses levodopa-induced dyskinesias in parkinsonian monkeys

The pathophysiology of L-Dopa-induced dyskinesias (LID), a common problem a fter long-term use of L-dopa in the treatment of Parkinson's disease (PD), is not completely understood. Oscillations in L-Dopa concentrations in the brain are believed to be responsible, at least in part, for their pathogene sis. This study was aimed at verifying whether chronic administration of ca bergoline, a long-acting dopamine D-2-like receptor agonist, can reverse es tablished LID. Four MPTP-treated cynomolgus monkeys with long-standing and stable parkinsonian syndrome and reproducible dyskinesias to L-Dopa, were u sed in this study. We compared the antiparkinsonian and dyskinetic response s of L-Dopa methyl ester (62.5 mg and 125 mg), given with benserazide (50 m g) (L-Dopa/benserazide), administered before and after a 6-week period duri ng which the animals were treated only by daily administration of cabergoli ne (doses ranging from 0.125 to 0.185 mg/kg, subcutaneous). During cabergol ine treatment, the monkeys initially showed marked dyskinesias, which were reduced significantly after 4 weeks of treatment. However, there was no tol erance to its antiparkinsonian effect. L-Dopa/benserazide given 4 days afte r cabergoline withdrawal produced a significant antiparkinsonian effect, bu t dyskinesias were dramatically reduced compared to what had been seen befo re chronic cabergoline treatment. The duration of the L-Dopa response was n ot increased after chronic administration of cabergoline. Our data suggest that sustained dopamine D-2 receptor stimulation could be of value when try ing to reduce or to reverse LID in patients with fluctuating advanced PD.