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

Objective: To determine whether dopamine (DA) D-1 or DA D-2 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 D-1 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 (D-2) and clozapine (D-1-D-2-like) was studied for comparison. Results: With the notable exception of the lowest dose of clozapine tested, coadministration of DA D-1 or D-2 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 D-4 (rather than D-1), serotonin, acetylcholine, and noradrenaline. Neither dyskinesias nor antiparkinsonian effects can be ascribed solely to the D-2 or D-1 receptor. Thus, some cooperation between the two receptors appears necessary for these behavioral effects.