Memantine selectively blocks extrasynaptic NMDA receptors in rat substantia nigra dopamine neurons

Brain Res. 2015 Apr 7;1603:1-7. doi: 10.1016/j.brainres.2015.01.041. Epub 2015 Feb 2.

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.

Keywords: Brain slice; DQP-1105; Extrasynaptic; MK-801; Synaptic; Whole-cell recording.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Dizocilpine Maleate / pharmacology
  • Dopaminergic Neurons / drug effects*
  • Dopaminergic Neurons / physiology
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Male
  • Memantine / pharmacology*
  • Membrane Potentials / drug effects
  • N-Methylaspartate / pharmacology
  • Patch-Clamp Techniques
  • Pyrazoles / pharmacology
  • Quinolones / pharmacology
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Substantia Nigra / drug effects*
  • Substantia Nigra / physiology
  • Tissue Culture Techniques

Substances

  • 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
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Pyrazoles
  • Quinolones
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Dizocilpine Maleate
  • Memantine