D1 receptor blockade improves l-dopa–induced dyskinesia but worsens parkinsonism in MPTP monkeys

Abstract

Objective: To determine whether dopamine (DA) D1 or DA D2 receptors are associated predominantly with the antiparkinsonian versus the dyskinetic effect of levodopa.Methods: The authors used four l-dopa–primed, dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed monkeys to test whether acute and selective blockade of the DA D1 receptor subtype, using SCH 23390 and NNC 01-112, could reduce l-dopa–induced dyskinesias without altering the relief of symptoms. Blockade of DA receptors using sulpiride (D2) and clozapine (D1–D2-like) was studied for comparison.Results: With the notable exception of the lowest dose of clozapine tested, coadministration of DA D1 or D2 antidopaminergic agents with l-dopa reduced the l-dopa–induced dyskinesias but also caused a return of parkinsonian disability. Prolonged latencies from intake of a single oral dose of l-dopa to turning “on,” decreased duration of the “on” state, and a complete failure to induce benefit was also observed.Conclusion: Low-dose clozapine could be an effective adjunct to reduce l-dopa–induced dyskinesias without altering the relief of parkinsonian symptoms. Interactions with many neurotransmitter systems may explain the better pharmacologic profile of clozapine, including DA D4 (rather than D1), serotonin, acetylcholine, and noradrenaline. Neither dyskinesias nor antiparkinsonian effects can be ascribed solely to the D2 or D1 receptor. Thus, some cooperation between the two receptors appears necessary for these behavioral effects.