Implication of NMDA receptors in the antidyskinetic activity of cabergoline, CI-1041, and Ro 61-8048 in MPTP monkeys with levodopa-induced dyskinesias.
This study assessed striatal N-methyl-D-aspartate (NMDA) glutamate receptors of 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys with levodopa (L-DOPA)-induced dyskinesias (LID). In a first experiment, four MPTP monkeys receiving L-DOPA/Benserazide alone developed dyskinesias. Four MPTP monkeys received L-DOPA/Benserazide plus CI-1041 an NMDA antagonist selective for NR1/NR2B and four were treated with L-DOPA/Benserazide plus a small dose of cabergoline; one monkey of each group developed mild dyskinesias at the end of treatment. In a second experiment, a kynurenine 3-hydroxylase inhibitor Ro 61-8048, combined with L-DOPA/Benserazide, reduced dyskinesias in MPTP monkeys. Drug-treated MPTP monkeys were compared to intact monkeys and saline-treated MPTP monkeys. Glutamate receptors were investigated by autoradiography using [(3)H]CGP-39653 (NR1/NR2A antagonist) and [(3)H]Ro25-6981 (NR1/NR2B antagonist). In general, striatal [(3)H]CGP-39653 specific binding was unaltered in all experimental groups. MPTP lesion decreased striatal [(3)H]Ro25-6981 specific binding; these levels were enhanced in the L-DOPA-alone-treated MPTP monkeys and decreased in antidyskinetic drugs treated monkeys. Maximal dyskinesias scores of the MPTP monkeys correlated significantly with [(3)H]Ro25-6981 specific binding in the rostral and caudal striatum. Hence, MPTP lesion, L-DOPA treatment and prevention of LID with CI-1041 and cabergoline, or reduction with Ro 61-8048 were associated with modulation of NR2B/NMDA glutamate receptors.
Ouattara
Bazoumana
B
Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, CHUL, 2705 Laurier Blvd, Quebec, QC, G1V 4G2, Canada.
Belkhir
Samah
S
Morissette
Marc
M
Dridi
Mehdi
M
Samadi
Pershia
P
Grégoire
Laurent
L
Meltzer
Leonard T
LT
Di Paolo
Thérèse
T
D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001545:Benserazide / Q000633:toxicity; D001583:Benzoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000077465:Cabergoline; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015259:Dopamine Agents / Q000633:toxicity; D018491:Dopamine Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D020820:Dyskinesias / Q000188:drug therapy; D004873:Ergolines / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000633:toxicity*; D020267:MPTP Poisoning / Q000378:metabolism*; D008252:Macaca fascicularis; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D001583:Benzoxazoles; D015259:Dopamine Agents; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D004873:Ergolines; D010880:Piperidines; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; C481484:besonprodil; D001545:Benserazide; D000077465:Cabergoline