Chronic CY 208–243 treatment of MPTP-monkeys causes regional changes of dopamine and GABAA receptors

Abstract

Four monkeys were rendered parkinsonian by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) i.v. administration and then treated chronically with increasing doses of the D1 agonist CY 208–243 (0.05, 0.1 and 0.5 mg/kg). All animals showed a dose-dependent improvement of their parkinsonian signs after the chronic CY 208–243 treatment; however, half of them developed peak-dose dyskinesias. Dopamine levels were more decreased in the striatum of MPTP-monkeys with dyskinesias compared to those without dyskinesias. [3H]SCH 23390 and [3H]SKF 38393 binding to D1 receptors were in general similar in the striatum of both groups of MPTP-monkeys except [3H]SKF 38393 binding which was lower in the posterior putamen of dyskinetic compared to non-dyskinetic monkeys reflecting decreased coupling of this receptor to G proteins. [3H]spiperone and [3H]N-n-propylnorapomorphine binding to D2 receptors in the striatum tended in general to be higher in dyskinetic compared to non-dyskinetic monkeys, and this reached statistical significance in the posterior caudate labelled with [3H]n-propylnorapomorphine. [3H]muscimol binding to GABAA receptors was significantly higher in the posterior caudate of dyskinetic compared to non-dyskinetic monkeys. The extent of striatal DA denervation, decreased D1, elevated D2 and GABAA receptors, as well as the decrease of the D1D2 receptor ratio in the posterior striatum may be involved in the appearance of dyskinesias after chronic CY 208–243 treatment.