Implication of NMDA receptors in the antidyskinetic activity of cabergoline, CI-1041, and Ro 61-8048 in MPTP monkeys with levodopa-induced dyskinesias.

Abstract

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.

• Authors: Bazoumana Ouattara, Samah Belkhir, Marc Morissette, Mehdi Dridi, Pershia Samadi, Laurent Grégoire, Leonard T Meltzer, Thérèse Di Paolo
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) Vol. 38 Issue 2 Pg. 128-42 (Jun 2009) ISSN: 0895-8696 [Print] United States
• PMID: 18704766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoxazoles
• Dopamine Agents
• Dopamine Agonists
• Dopamine Plasma Membrane Transport Proteins
• Ergolines
• Piperidines
• Receptors, Glutamate
• Receptors, N-Methyl-D-Aspartate
• Levodopa
• besonprodil
• Benserazide
• Cabergoline

Topics

• Animals
• Autoradiography
• Behavior, Animal (drug effects, physiology)
• Benserazide (toxicity)
• Benzoxazoles (pharmacology, therapeutic use)
• Cabergoline
• Corpus Striatum (drug effects, metabolism, pathology)
• Dopamine Agents (toxicity)
• Dopamine Agonists (pharmacology, therapeutic use)
• Dopamine Plasma Membrane Transport Proteins (metabolism)
• Dyskinesias (drug therapy)
• Ergolines (pharmacology, therapeutic use)
• Female
• Humans
• Levodopa (toxicity)
• MPTP Poisoning (metabolism)
• Macaca fascicularis
• Ovariectomy
• Piperidines (pharmacology, therapeutic use)
• Receptors, Glutamate (metabolism)
• Receptors, N-Methyl-D-Aspartate (metabolism)