Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal

Am J Psychiatry. 1998 Jun;155(6):726-32. doi: 10.1176/ajp.155.6.726.


Objective: Neurophysiological and pathological effects of ethanol may be mediated, to an important extent, via the glutamatergic system. Animal studies indicate the acute effects of ethanol disrupt glutamatergic neurotransmission by inhibiting the response of the N-methyl-D-aspartate (NMDA) receptor. Persistent attenuation of glutamatergic neurotransmission by chronic ethanol exposure results in the compensatory up-regulation of NMDA receptors. Whether glutamatergic neurotransmission and oxidative stress are enhanced during ethanol withdrawal in humans is unknown.

Method: CSF was obtained from 18 matched comparison subjects and from 18 patients with alcohol dependence 1 week and 1 month after cessation of ethanol ingestion. CSF samples were analyzed for excitatory neurotransmitters, gamma-aminobutyric acid (GABA), and markers for oxidative stress.

Results: The alcohol-dependent patients' CSF levels of aspartate, glycine, and N-acetylaspartylglutamate were all higher than those of the comparison subjects, and their concentration of GABA was lower. In addition, there were significant correlations between excitatory neurotransmitters and oxidative stress markers, which suggest that the two mechanisms may play an interactive role in neurotoxicity mediated by ethanol withdrawal.

Conclusions: The data suggest that augmentation of excitatory neurotransmission may lead to enhanced oxidative stress, which, in concert with reduced inhibitory neurotransmission, may contribute to the symptoms of ethanol withdrawal and associated neurotoxicity in humans. Whether these abnormalities represent a trait- or state-dependent marker of ethanol dependence remains to be resolved.

Publication types

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

MeSH terms

  • Adult
  • Alcoholism / metabolism
  • Alcoholism / physiopathology*
  • Aspartic Acid / metabolism
  • Aspartic Acid / physiology
  • Dipeptides / metabolism
  • Dipeptides / physiology
  • Ethanol / adverse effects*
  • Ethanol / pharmacology
  • Excitatory Amino Acids / metabolism
  • Excitatory Amino Acids / physiology
  • Female
  • Glutamates / metabolism
  • Glutamates / physiology*
  • Humans
  • Male
  • Middle Aged
  • Oxidative Stress / physiology*
  • Receptors, Glutamate / metabolism
  • Receptors, Glutamate / physiology
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Substance Withdrawal Syndrome / metabolism
  • Substance Withdrawal Syndrome / physiopathology*
  • Superoxide Dismutase / cerebrospinal fluid
  • Superoxide Dismutase / metabolism
  • Synaptic Transmission / physiology*
  • Up-Regulation / drug effects
  • gamma-Aminobutyric Acid / metabolism
  • gamma-Aminobutyric Acid / physiology


  • Dipeptides
  • Excitatory Amino Acids
  • Glutamates
  • Receptors, Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • isospaglumic acid
  • Aspartic Acid
  • Ethanol
  • gamma-Aminobutyric Acid
  • Superoxide Dismutase