The enigma of fetal alcohol neurotoxicity

John W. Olney, David F. Wozniak, Nuri B. Farber, Vesna Jevtovic-Todorovic, Petra Bittigau, Chrysanthy Ikonomidou

Research output: Contribution to journalReview articlepeer-review

91 Scopus citations


The neurotoxic effects of ethanol on the human fetal brain (fetal alcohol syndrome, FAS) have been recognized for three decades, but the underlying mechanisms have remained elusive. Recently, we discovered that a single episode of ethanol intoxication lasting for several hours can trigger a massive wave of apoptotic neurodegeneration in the developing rat or mouse brain. The window of vulnerability coincides with the developmental period of synaptogenesis, also known as the brain growth-spurt period, which in rodents is a postnatal event, but in humans extends from the sixth month of gestation to several years after birth. We propose that the N-methyl-D-aspartate (NMDA) antagonist and gamma-aminobutyric (GABA)mimetic properties of ethanol are responsible for its apoptogenic action, in that we have found that other drugs that block NMDA glutamate receptors or mimic GABA at GABAA receptors also trigger apoptotic neurodegeneration in the developing brain. Our findings have clinical significance, not only because they can explain the reduced brain mass and neurobehavioral disturbances associated with the human FAS, but because many agents in the human environment, other than ethanol, have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers [phencyclidine (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines], and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).

Original languageEnglish
Pages (from-to)109-119
Number of pages11
JournalAnnals of Medicine
Issue number2
StatePublished - 2002


  • Alcohol
  • Apoptosis
  • Ethanol
  • Fetal alcohol syndrome
  • GABA
  • Glutamate
  • Neurodegeneration


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