Evidence for a role of the N-methyl-D-aspartate (NMDA) receptor in cortical spreading depression in the rat

Brain Res. 1988 Aug 9;457(2):226-40. doi: 10.1016/0006-8993(88)90690-7.


The neurotransmitter glutamate activates the N-methyl-D-aspartate (NMDA), quisqualate and kainate receptors. It has been proposed, but also disputed, that local release of glutamate would play a pivotal role in cortical spreading depression (SD). We tested this hypothesis by investigating the influence of NMDA antagonists on SD, using the non-competitive NMDA antagonists ketamine, phencyclidine (PCP) and MK-801 and the competitive NMDA antagonist DL-2-amino-7-phosphonoheptanoate (2-APH), injected intraperitoneally in rats anesthetized with alfentanil. SD was elicited by cathodal DC-stimulation of the frontal cortex. SD propagation was followed using two ion-sensitive microelectrodes placed in the parietal and occipital cortex. The NMDA antagonists increased SD threshold, decreased the propagation velocity and decreased the duration of the accompanying extracellular DC, K+ and Ca2+ changes at the following doses: 40 mg/kg ketamine, 10 mg/kg PCP, 0.63 mg/kg MK-801, 10 and 40 mg/kg 2-APH. With each NMDA antagonist failure of SD propagation between both microelectrodes could be observed. SD elicitation (or propagation) was inhibited completely with 80 mg/kg ketamine, 3.1 mg/kg MK-801 and 160 mg/kg 2-APH. These NMDA antagonists have also anticonvulsant properties. None of these effects on SD were observed with high doses of other anticonvulsants such as 80 mg/kg phenytoin or 40 mg/kg diazepam. These experiments indicate that endogenous release of excitatory amino acids and their action on the NMDA receptor play an important role in the initiation, propagation and duration of SD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate* / analogs & derivatives*
  • Amino Acids / pharmacology
  • Animals
  • Anticonvulsants / pharmacology*
  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / antagonists & inhibitors
  • Cortical Spreading Depression / drug effects*
  • Diazepam / pharmacology
  • Dibenzocycloheptenes / pharmacology
  • Dizocilpine Maleate
  • Ketamine / pharmacology
  • Male
  • N-Methylaspartate
  • Phencyclidine / pharmacology
  • Phenytoin / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter / physiology*


  • Amino Acids
  • Anticonvulsants
  • Dibenzocycloheptenes
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Neurotransmitter
  • Aspartic Acid
  • Phenytoin
  • N-Methylaspartate
  • Ketamine
  • Dizocilpine Maleate
  • 2-Amino-5-phosphonovalerate
  • Phencyclidine
  • 2-amino-7-phosphonoheptanoic acid
  • Diazepam