GluN2A and GluN2B NMDA Receptor Subunits Differentially Modulate Striatal Output Pathways and Contribute to Levodopa-Induced Abnormal Involuntary Movements in Dyskinetic Rats

• Published in: ACS chemical neuroscience Vol. 4; no. 5; pp. 808 - 816
• Main Authors: Mabrouk, Omar S, Mela, Flora, Calcagno, Mariangela, Budri, Mirco, Viaro, Riccardo, Dekundy, Andrzej, Parsons, Christopher G, Auberson, Yves P, Morari, Michele
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 15-05-2013
• Subjects: Animals; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine - metabolism; Dopamine Agents - adverse effects; Dyskinesia, Drug-Induced - etiology; gamma-Aminobutyric Acid - drug effects; gamma-Aminobutyric Acid - metabolism; Globus Pallidus - drug effects; Globus Pallidus - metabolism; Glutamic Acid - drug effects; Glutamic Acid - metabolism; Levodopa - adverse effects; Male; Microdialysis; Neostriatum - drug effects; Neostriatum - metabolism; Oxidopamine - adverse effects; Phenols - pharmacology; Piperidines - pharmacology; Quinoxalines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - physiology; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Ro 25-6981; GABA; 6-OHDA; NMDA receptor subunits; microdialysis; NVP-AAM077
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/cn400016d

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.