CHRONIC CY 208-243 TREATMENT OF MPTP-MONKEYS CAUSES REGIONAL CHANGES OF DOPAMINE AND GABA(A) RECEPTORS

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 D-1 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, [H-3]SCH 23390 and [H-3]SKF 38393 binding to D-1 receptors were in general similar in the striatum of both groups of MPTP-monkeys except [H-3]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. [H-3]spiperone and [H-3]N-n-propylnorapomorphine binding to D-2 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 [H-3]n-propylnorapomorphine. [H-3]muscimol binding to GABA(A) receptors was significantly higher in the posterior caudate of dyskinetic compared to non-dyskinetic monkeys. The extent of striatal DA denervation, decreased D-1, elevated D-2 and GABA(A) receptors, as well as the decrease of the D-1/D-2 receptor ratio in the posterior striatum may be involved in the appearance of dyskinesias after chronic CY 208-243 treatment.