title: NMDA receptor antagonism potentiates the L-DOPA-induced extracellular dopamine release in the subthalamic nucleus of hemi-parkinson rats.
abstract: Long term treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is associated with several motor complications. Clinical improvement of this treatment is therefore needed. Lesions or high frequency stimulation of the hyperactive subthalamic nucleus (STN) in Parkinson's disease (PD), alleviate the motor symptoms and reduce dyskinesia, either directly and/or by allowing the reduction of the L-DOPA dose. N-methyl-D-aspartate (NMDA) receptor antagonists might have similar actions. However it remains elusive how the neurochemistry changes in the STN after a separate or combined administration of L-DOPA and a NMDA receptor antagonist. By means of in vivo microdialysis, the effect of L-DOPA and/or MK 801, on the extracellular dopamine (DA) and glutamate (GLU) levels was investigated for the first time in the STN of sham and 6-hydroxydopamine-lesioned rats. The L-DOPA-induced DA increase in the STN was significantly higher in DA-depleted rats compared to shams. MK 801 did not influence the L-DOPA-induced DA release in shams. However, MK 801 enhanced the L-DOPA-induced DA release in hemi-parkinson rats. Interestingly, the extracellular STN GLU levels remained unchanged after nigral degeneration. Furthermore, administration of MK 801 alone or combined with L-DOPA did not alter the STN GLU levels in both sham and DA-depleted rats. The present study does not support the hypothesis that DA-ergic degeneration influences the STN GLU levels neither that MK 801 alters the GLU levels in lesioned and non-lesioned rats. However, NMDA receptor antagonists could be used as a beneficial adjuvant treatment for PD by enhancing the therapeutic efficacy of l-DOPA at least in part in the STN.
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Electronic address: aelarfan@vub.ac.be.
authors.forename: Anissa
authors.initials: A
authors.lastname: El Arfani
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium; Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Electronic address: Eduard-Mihai.Bentea@vub.ac.be.
authors.forename: Eduard
authors.initials: E
authors.lastname: Bentea
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Electronic address: Najat.Aourz@vub.ac.be.
authors.forename: Najat
authors.initials: N
authors.lastname: Aourz
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Electronic address: BenAmpe@uzbrussel.be.
authors.forename: Ben
authors.initials: B
authors.lastname: Ampe
authors.affiliation: Unité Mixte de Recherche, Centre National de la Recherche Scientifique (UMR-CNRS) 5227, Université de Bordeaux, 146 rue Léo Saignat, B.P. 28, 33076 Bordeaux Cedex, France. Electronic address: deurwaer@u-bordeaux2.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: De Deurwaerdère
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Electronic address: aveeckha@vub.ac.be.
authors.forename: Ann
authors.initials: A
authors.lastname: Van Eeckhaut
authors.affiliation: Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Electronic address: amassie@vub.ac.be.
authors.forename: Ann
authors.initials: A
authors.lastname: Massie
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Electronic address: Sophie.Sarre@apb.be.
authors.forename: Sophie
authors.initials: S
authors.lastname: Sarre
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Electronic address: Ilse.Smolders@vub.ac.be.
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information, Center for Neuroscience, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. Electronic address: ymichot@vub.ac.be.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D007839:Functional Laterality; D018698:Glutamic Acid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000503:physiopathology; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology; D020531:Subthalamic Nucleus / Q000187:drug effects* / Q000503:physiopathology
chemical_list: D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007980:Levodopa; D016291:Dizocilpine Maleate; D016627:Oxidopamine; D004298:Dopamine
keywords: 6-OHDA rat model; Dopamine; In vivo microdialysis; NMDA receptor antagonist; Subthalamic nucleus; l-DOPA