title: GluN2A and GluN2B NMDA receptor subunits differentially modulate striatal output pathways and contribute to levodopa-induced abnormal involuntary movements in dyskinetic rats.
abstract: Dual probe microdialysis was used to investigate whether GluN2A and GluN2B NMDA receptor subunits regulate striatal output pathways under dyskinetic conditions. The preferential GluN2A antagonist NVP-AAM077 perfused in the dopamine-depleted striatum of 6-hydroxydopamine hemilesioned dyskinetic rats reduced GABA and glutamate levels in globus pallidus whereas the selective GluN2B antagonist Ro 25-6981 elevated glutamate without affecting pallidal GABA. Moreover, intrastriatal NVP-AAM077 did not affect GABA but elevated glutamate levels in substantia nigra reticulata whereas Ro 25-6981 elevated GABA and reduced nigral glutamate. To investigate whether GluN2A and GluN2B NMDA receptor subunits are involved in motor pathways underlying dyskinesia expression, systemic NVP-AAM077 and Ro 25-6981 were tested for their ability to attenuate levodopa-induced abnormal involuntary movements. NVP-AAM077 failed to prevent dyskinesia while Ro 25-6981 mildly attenuated it. We conclude that in the dyskinetic striatum, striatal GluN2A subunits tonically stimulate the striato-pallidal pathway whereas striatal GluN2B subunits tonically inhibit striato-nigral projections. Moreover, GluN2A subunits are not involved in dyskinesia expression whereas GluN2B subunits minimally contribute to it.
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, Ferrara, Italy.
authors.forename: Omar S
authors.initials: OS
authors.lastname: Mabrouk
authors.forename: Flora
authors.initials: F
authors.lastname: Mela
authors.forename: Mariangela
authors.initials: M
authors.lastname: Calcagno
authors.forename: Mirco
authors.initials: M
authors.lastname: Budri
authors.forename: Riccardo
authors.initials: R
authors.lastname: Viaro
authors.forename: Andrzej
authors.initials: A
authors.lastname: Dekundy
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Parsons
authors.forename: Yves P
authors.initials: YP
authors.lastname: Auberson
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000009:adverse effects; D004409:Dyskinesia, Drug-Induced / Q000209:etiology; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine / Q000009:adverse effects; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism*
chemical_list: D004298:Dopamine; D015259:Dopamine Agents; D018698:Glutamic Acid; D007980:Levodopa; D016627:Oxidopamine; D010636:Phenols; D010880:Piperidines; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; C498554:5-(alpha-methyl-4-bromobenzylamino)phosphonomethyl-1,4-dihydroquinoxaline-2,3-dione; C121001:NR2B NMDA receptor; C109643:Ro 25-6981