title: Memantine block depends on agonist presentation at the NMDA receptor in substantia nigra pars compacta dopamine neurones.
abstract: NMDA glutamate receptors (NMDARs) have critical functional roles in the nervous system but NMDAR over-activity can contribute to neuronal damage. The open channel NMDAR blocker, memantine is used to treat certain neurodegenerative diseases, including Parkinson's disease (PD) and is well tolerated clinically. We have investigated memantine block of NMDARs in substantia nigra pars compacta (SNc) dopamine neurones, which show severe pathology in PD. Memantine (10 μM) caused robust inhibition of whole-cell (synaptic and extrasynaptic) NMDARs activated by NMDA at a high concentration or a long duration, low concentration. Less memantine block of NMDAR-EPSCs was seen in response to low frequency synaptic stimulation, while responses to high frequency synaptic stimulation were robustly inhibited by memantine; thus memantine inhibition of NMDAR-EPSCs showed frequency-dependence. By contrast, MK-801 (10 μM) inhibition of NMDAR-EPSCs was not significantly different at low versus high frequencies of synaptic stimulation. Using immunohistochemistry, confocal imaging and stereological analysis, NMDA was found to reduce the density of cells expressing tyrosine hydroxylase, a marker of viable dopamine neurones; memantine prevented the NMDA-evoked decrease. In conclusion, memantine blocked NMDAR populations in different subcellular locations in SNc dopamine neurones but the degree of block depended on the intensity of agonist presentation at the NMDAR. This profile may contribute to the beneficial effects of memantine in PD, as glutamatergic activity is reported to increase, and memantine could preferentially reduce over-activity while leaving some physiological signalling intact.
authors.affiliation: Department of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Wild
authors.forename: E
authors.initials: E
authors.lastname: Akyol
authors.forename: S L C
authors.initials: SL
authors.lastname: Brothwell
authors.forename: P
authors.initials: P
authors.lastname: Kimkool
authors.forename: J N
authors.initials: JN
authors.lastname: Skepper
authors.forename: A J
authors.initials: AJ
authors.lastname: Gibb
authors.forename: S
authors.initials: S
authors.lastname: Jones
mesh_terms: D000818:Animals; D002452:Cell Count; D016291:Dizocilpine Maleate / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D008559:Memantine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009410:Nerve Degeneration / Q000517:prevention & control; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D014446:Tyrosine 3-Monooxygenase; D008559:Memantine
keywords: Excitotoxicity; Use-dependent antagonist