Effect of D1 and D2 agonists and antagonists on dyskinesia produced by L-dopa in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys

Abstract

A group of five cynomolgus monkeys was rendered parkinsonian by the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then treated daily with levodopa until all animals developed evident dyskinesia in the limbs after each dose. At this point, levodopa was replaced by selective D2 and D1 dopamine receptor agonists. All D2 agonists including quinpirole, (+)-4-propyl-9-hydroxynaphthoxazine, bromocriptine, terguride and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperone reproduced the same dyskinesia, the intensity and duration of which was dose-dependent and paralleled the therapeutic effect. One D1 agonist, SFK-38393, was without effect (antiparkinsonian and dyskinetic) whereas another, CY-208243, induced antiparkinsonian at a low dose but also a dyskinetic effect at a higher dose. The effect of the selective agonists were antagonized completely by their corresponding antagonist but partially by the noncorresponding one. The effect of either D1 and D2 agonist was totally suppressed by the dopamine depleting agent alpha-methyl-p-tyrosine, but the effect was restored by a small subthreshold dose of the other (complementary) agonist. Our results thus indicate that dyskinesia cannot be ascribed solely to the D2 or the D1 receptor and that some cooperation between the two receptors appears necessary for their manifestation.