CABERGOLINE, A LONG-ACTING DOPAMINE D-2-LIKE RECEPTOR AGONIST, PRODUCES A SUSTAINED ANTIPARKINSONIAN EFFECT WITH TRANSIENT DYSKINESIAS IN PARKINSONIAN DRUG-NAIVE PRIMATES

Continuous dopaminergic receptor stimulation is now considered as an i nteresting approach for the control of motor complications often seen in parkinsonian patients treated chronically with levodopa. Cabergolin e, which is a long-acting dopamine D-2-like receptor agonist, has been tried recently with good results as an adjunct in patients already on levodopa-therapy. Thus, the present study was designed to test the ef fects of repeated s.c administration of cabergoline as sole therapeuti c agent during a month in 3 drug-naive MPTP parkinsonian monkeys to se e whether or not cabergoline, given every other day at 0.25 mg/kg, wou ld have a sustained antiparkinsonian effect and would induce dyskinesi as. The animals were rated to quantify the antiparkinsonian as well as the dyskinetic response and gross locomotor activity was monitored by photocells. The averaged locomotor response, initially greatly increa sed (similar to 9 times higher than after saline treatment in the same animals), decreased by similar to 50% after 2 weeks but was thereafte r maintained at this level until the end of the study. The parkinsonia n features were improved in a sustained manner in all monkeys and tran sient dyskinesias (week 1 and 2) were present in 2 of 3 monkeys. After sacrifice receptor binding assays were performed on striatal and pall idal tissues homogenates with tritiated selective ligands and compared with those of 3 normal and 3 MPTP-exposed monkeys otherwise untreated . A significant decrease in dopamine D-2-like receptor density in the putamen (- 36% on average vs. untreated MPTP-exposed monkeys) may be i nvolved in the behavioral partial tolerance to antiparkinsonian effect of cabergoline and the disappearance of dyskinesias. A reversal of th e supersensitivity of GABA(A) receptor in the internal segment of the globus pallidus (-15% on average vs. untreated MPTP-exposed monkeys) m ay also be implicated in this latter behavioral effect.