Glutamate, NMDA, and AMPA induced changes in extracellular space volume and tortuosity in the rat spinal cord

J Cereb Blood Flow Metab. 2001 Sep;21(9):1077-89. doi: 10.1097/00004647-200109000-00005.


Glutamate release, particularly in pathologic conditions, may result in cellular swelling. The authors studied the effects of glutamate, N-methyl-D-aspartate (NMDA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) on extracellular pH (pH(e)), extracellular potassium concentration ([K(+)](e)), and changes in extracellular space (ECS) diffusion parameters (volume fraction alpha, tortuosity lambda) resulting from cellular swelling. In the isolated spinal cord of 4-to 12-day-old rats, the application of glutamate receptor agonists induced an increase in [K(+)](e), alkaline-acid shifts, a substantial decrease in alpha, and an increase in lambda. After washout of the glutamate receptor agonists, alpha either returned to or overshot normal values, whereas lambda remained elevated. Pretreatment with 20 mmol/L Mg(++), MK801, or CNQX blocked the changes in diffusion parameters, [K(+)](e) and pH(e) evoked by NMDA or AMPA. However, the changes in diffusion parameters also were blocked in Ca(2+)-free solution, which had no effect on the [K(+)](e) increase or acid shift. The authors conclude that increased glutamate release may produce a large, sustained and [Ca(2+)](e)-dependent decrease in alpha and increase in lambda. Repetitive stimulation and pathologic states resulting in glutamate release therefore may lead to changes in ECS volume and tortuosity, affecting volume transmission and enhancing glutamate neurotoxicity and neuronal damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Animals
  • Calcium / pharmacology
  • Cell Death / drug effects
  • Chelating Agents / pharmacology
  • Diffusion
  • Dizocilpine Maleate / pharmacology
  • Edema / pathology
  • Egtazic Acid / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Extracellular Space / drug effects
  • Extracellular Space / metabolism
  • Gliosis / metabolism
  • Gliosis / pathology
  • Glutamic Acid / pharmacology*
  • Hydrogen-Ion Concentration
  • In Vitro Techniques
  • Magnesium / pharmacology
  • N-Methylaspartate / pharmacology*
  • Potassium / metabolism
  • Rats
  • Rats, Wistar
  • Spinal Cord / drug effects*
  • Spinal Cord / metabolism
  • Spinal Cord / pathology*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology*


  • Chelating Agents
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Glutamic Acid
  • Egtazic Acid
  • N-Methylaspartate
  • Dizocilpine Maleate
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • Magnesium
  • Potassium
  • Calcium