title: Memantine selectively blocks extrasynaptic NMDA receptors in rat substantia nigra dopamine neurons.
abstract: Recent studies suggest that selective block of extrasynaptic N-methyl-d-aspartate (NMDA) receptors might protect against neurodegeneration. We recorded whole-cell currents with patch pipettes to characterize the ability of memantine, a low-affinity NMDA channel blocker, to block synaptic and extrasynaptic NMDA receptors in substantia nigra zona compacta (SNC) dopamine neurons in slices of rat brain. Pharmacologically isolated NMDA receptor-mediated EPSCs were evoked by electrical stimulation, whereas synaptic and extrasynaptic receptors were activated by superfusing the slice with NMDA (10 µM). Memantine was 15-fold more potent for blocking currents evoked by bath-applied NMDA compared to synaptic NMDA receptors. Increased potency for blocking bath-applied NMDA currents was shared by the GluN2C/GluN2D noncompetitive antagonist DQP-1105 but not by the high-affinity channel blocker MK-801. Our data suggest that memantine causes a selective block of extrasynaptic NMDA receptors that are likely to contain GluN2C/2D subunits. Our results justify further investigations on the use of memantine as a neuroprotective agent in Parkinson's disease.
authors: Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors: Yan-Na
authors: YN
authors: Wu
authors: Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA; Veterans Affairs Portland Health Care System, Portland, OR 97207, USA. Electronic address: johnsost@ohsu.edu.
authors: Steven W
authors: SW
authors: Johnson
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects* / Q000502:physiology; D046509:Tissue Culture Techniques
chemical_list: C568654:4-(5-(4-bromophenyl)-3-(6-methyl-2-oxo-4-phenyl-1,2-dihydroquinolin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011720:Pyrazoles; D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D008559:Memantine
keywords: Brain slice; DQP-1105; Extrasynaptic; MK-801; Synaptic; Whole-cell recording