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.