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

From the Neuroscience Research Unit, CHUL Research Centre; and the Department of Medicine, Faculty of Medicine, Laval University, Ste-Foy (Quebec), Canada.

Address correspondence and reprint requests to Dr. Paul J. Bédard, Unité de Recherche en Neuroscience, Centre de Recherche du CHUQ, Pavillon CHUL, RC 9800, 2705, Boulevard Laurier, Ste-Foy (Québec), G1V 4G2, Canada.

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.

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