Nine monkeys (Macaca fascicularis) were rendered parkinsonian after
intravenous administration of the toxin
MPTP. Three of these animals received pulsatile administration of the D1 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-dyskinetic 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, Bmax of D1 receptors labeled with [3H]
SCH 23390 were increased versus untreated
MPTP-monkeys with no change in Kd. 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 [3H]
spiperone 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 D1 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.