title: Investigation of the antidyskinetic site of action of metabotropic and ionotropic glutamate receptor antagonists. Intracerebral infusions in 6-hydroxydopamine-lesioned rats with levodopa-induced dyskinesia.
abstract: Long-term levodopa replacement therapy in Parkinson's disease is confounded by abnormal involuntary movements, known as levodopa induced dyskinesia (LID). Dysfunctional glutamatergic neurotransmission has been implicated in the pathogenesis of LID making metabotropic and ionotropic glutamate receptors attractive novel therapeutic targets. The objective of the present study was to investigate the antidyskinetic site of action of different glutamate receptor antagonists in the brain. For that purpose, metabotropic glutamate subtype 5 (3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride, MTEP), NMDA NR2B selective ((aR,bS)-a-(4-Hydroxyphenyl)-b-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate, Ro 25-6981) and AMPA (2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt, NBQX) receptor antagonists or saline were administered by intracerebral infusion in the caudate-putamen (CPu), the substantia nigra zona reticulata (SNr) or the subthalamic nucleus (STN) of 6-hydroxydopamine-lesioned rats exhibiting LID. Dyskinesia was assessed with the modified version of the rat Abnormal Involuntary Movements scale (AIMS). Ro 25-6981 and to a lesser extent NBQX improved dyskinesia (82% and 19% reduction in AIM score respectively) after infusion in the caudate-putamen. None of the three drugs managed to noticeably reduce AIM score after infusion in the SNr. MTEP was the only drug that produced a reduction in AIM score (48%) when infused in STN. In conclusion, while the striatum proved important in the antidyskinetic action of NMDA and AMPA receptor antagonists, the results of this study highlight also the importance of the metabotropic glutamate receptors that reside in the STN as therapeutic targets in the treatment of LID.
authors.affiliation: Department of Neurology, Medical School, University of Ioannina, Ioannina, Greece. smaranis@cc.uoi.gr
authors.forename: Sotirios
authors.initials: S
authors.lastname: Maranis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Stamatis
authors.forename: Christos
authors.initials: C
authors.lastname: Tsironis
authors.forename: Spiridon
authors.initials: S
authors.lastname: Konitsiotis
mesh_terms: D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D057967:Infusions, Intraventricular; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D016627:Oxidopamine; D010636:Phenols / Q000008:administration & dosage / Q000627:therapeutic use; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use; D011699:Putamen / Q000187:drug effects; D011810:Quinoxalines / Q000008:administration & dosage / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013378:Substantia Nigra / Q000187:drug effects; D020531:Subthalamic Nucleus / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: C541428:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)piperidine; D018726:Anti-Dyskinesia Agents; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D011810:Quinoxalines; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D013844:Thiazoles; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D007980:Levodopa; D016627:Oxidopamine