Dyskinesias and tolerance induced by chronic treatment with a D1 agonist administered in pulsatile or continuous mode do not correlate with changes of putaminal D1 receptors in drug-naive MPTP monkeys

Abstract

Nine monkeys ( Macaca fascicularis) were rendered parkinsonian after intravenous administration of the toxin MPTP. Three of these animals received pulsatile administration of the D 1 receptor agonist SKF 82958 (1 mg/kg, three times daily) while three were treated by continuous infusion via an osmotic mini-pump with SKF 82958 (at an equivalent amount daily) for 29 days. Untreated MPTP as well as healthy control animals were also studied. Relief of parkinsonian symptoms was observed in the three animals of the pulsatile group. However, dyskinesia occurred in two monkeys which had striatal dopamine depletion of > 99% compared to the non-dyskinesic animal slightly less denervated (94%). Monkeys receiving continuous SKF 82958 showed no anti-parkinsonian effect and no dyskinesia. All monkeys from the pulsatile and continuous group had measurable amount of plasma SKF 82958 as assayed by HPLC with electrochemical detection. In the putamen of all SKF 82958-treated monkeys, B max of Dl receptors labeled with [ 3HISCH 23390 were increased versus untreated MPTP-monkeys with no change in K d. In contrast, a decrease D1 receptor density was observed in the nucleus accumbens of untreated MPTP monkeys versus controls and this was not corrected with either pulsatile or continuous SKF 82958 treatments. D2 receptor density measured with [ 3Hlspiperone binding was increased in the posterior putamen of SKF 82958-treated monkeys whereas no change was observed in the accumbens compared to control animals. Hence, tolerance with the continuous administration of a DI agonist is not associated with a decrease of putaminal D1 or D2 receptor densities and dyskinesia could not be specifically associated with an increase of putaminal D1 receptors.