Antidyskinetic effect of JL-18, a clozapine analog, in parkinsonian monkeys.
Clozapine reduces L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesias in parkinsonian patients. To test if the antidyskinetic effect of clozapine is related to antagonism at the dopamine D(4) receptor, we investigated the effect of 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1, 4]benzodiazepine (JL-18), a structural analog of clozapine which is more selective for this receptor. Four 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-Dopa were used in this study. They were injected subcutaneously (s.c.) with L-Dopa methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-Dopa/benserazide) alone or in combination with JL-18 (at the doses of 0.1, 0.3, or 0.9 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-Dopa/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of JL-18, at low doses (0.1, 0.3 mg/kg) with L-Dopa/benserazide, produced a dose-dependent reduction in L-Dopa-induced dyskinesias without a parallel return to parkinsonism. The present results suggest that novel selective dopamine D(4) receptor antagonists may represent a useful tool to reduce L-Dopa-induced dyskinesias.
Hadj Tahar
A
A
Department of Medicine, Faculty of Medicine and Neuroscience Research Unit, Laval University Research Center, 2705 Boul. Laurier, Ste-Foy, G1V 4G2, Quebec, Canada.
Bélanger
N
N
Bangassoro
E
E
Grégoire
L
L
Bédard
P J
PJ
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001545:Benserazide / Q000494:pharmacology; D003024:Clozapine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D005260:Female; D007980:Levodopa / Q000494:pharmacology; D008252:Macaca fascicularis; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology
D000978:Antiparkinson Agents; C093454:JL 18; D007980:Levodopa; D001545:Benserazide; D003024:Clozapine