title: Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys.
abstract: Metabotropic glutamate 5 (mGlu5) receptor antagonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LID) in Parkinson's disease (PD). The aim of this study was to investigate the long-term effect of the prototypal mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on glutamate receptors known to be involved in the development of LID in the de novo chronic treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP monkeys were treated for one month with L-DOPA and developed dyskinesias while those treated with L-DOPA and MPEP (10 mg/kg) developed significantly less. Normal control and saline-treated MPTP monkeys were also included. All MPTP monkeys were extensively and similarly denervated. The basal ganglia [(3)H]ABP688 specific binding (mGlu5 receptors) was elevated in L-DOPA-treated MPTP monkeys compared to controls but not in those treated with L-DOPA and MPEP; dyskinesia scores of these monkeys correlated positively with their [(3)H]ABP688 specific binding. Striatal density (B(max)) of [(3)H]ABP688 specific binding increased in L-DOPA-treated MPTP monkeys compared to other groups and affinity (Kd) remained unchanged. Striatal mGlu5 receptor mRNA remained unchanged following treatments. Elevated basal ganglia specific binding of [(3)H]Ro 25-6981 (NMDA NR1/NR2B receptors), [(3)H]Ro 48-8587 (AMPA receptors) but not [(3)H]CGP-39653 (NMDA NR1/NR2A receptors) was observed only in L-DOPA-treated MPTP monkeys; dyskinesias scores correlated with binding. By contrast, basal ganglia [(3)H]LY341495 specific binding (mGlu2/3 receptors) decreased in L-DOPA-treated MPTP monkeys compared to controls, saline and L-DOPA + MPEP treated MPTP monkeys; dyskinesias scores correlated negatively with this binding. Hence, chronic MPEP treatment reduces the development of LID and is associated with a normalization of glutamate neurotransmission.
authors.affiliation: Neuroscience Research Unit, Laval University Medical Center (CHUQ), Quebec, QC, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Morin
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.forename: Laurent
authors.initials: L
authors.lastname: Grégoire
authors.forename: Baltazar
authors.initials: B
authors.lastname: Gomez-Mancilla
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives; D000596:Amino Acids; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D005260:Female; D007093:Imidazoles; D007980:Levodopa / Q000009:adverse effects*; D008252:Macaca fascicularis; D010091:Oximes; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism*; D010636:Phenols; D010880:Piperidines; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines; D011869:Radioligand Assay; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014316:Tritium; D014966:Xanthenes
chemical_list: C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; D000596:Amino Acids; D007093:Imidazoles; C114624:LY 341495; D010091:Oximes; D010636:Phenols; D010880:Piperidines; D011725:Pyridines; D011799:Quinazolines; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; C112933:Ro 48-8587; D014966:Xanthenes; D014316:Tritium; C069052:CGP 39653; D007980:Levodopa; D015763:2-Amino-5-phosphonovalerate; C121465:6-methyl-2-(phenylethynyl)pyridine
keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2-methyl-6-(phenylethynyl)pyridine; 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine; 6-OHDA; 6-hydroxydopamine; AMPA; AMPA receptor; B(max); DA; DL; DM; GP; GPe; GPi; K(d); LID; MPEP; MPTP; MTEP; N-methyl-d-aspartate; NMDA; NMDA receptor; PD; Parkinson's disease; VL; VM; affinity; density; dopamine; dorsolateral; dorsomedial; external globus pallidus; globus pallidus; internal globus pallidus; l-3,4-dihydroxyphenylalanine; l-DOPA; l-DOPA-induced dyskinesias; mGlu; mGlu2/3 receptor; mGlu5 receptor; metabotropic glutamate; ventrolateral; ventromedial; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid