Summary And Conclusions

Ethanol is a simple molecule that freely enters the brain and interacts with many cellular or subcellular systems. Recent research suggests that its acute intoxicating effects and its ability to induce more permanent deleterious effects in the brain may be due to its interaction with ion channels through which many of the brain's normal functions are mediated. Of particular importance are ion channels associated with neurotransmitter function, especially channels that mediate the excitatory actions of glutamate and those that mediate the inhibitory actions of GABA. Recent evidence indicates that ethanol, by a dual mechanism (blockade of NMDA glutamate receptor ion channels and excessive activation of GABAA channels), can trigger widespread apoptotic neurodegeneration in many regions of the developing brain. This is a mechanism that can explain the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome.

Mechanisms operative in the adult brain are different from those operative in the developing brain Wernicke's encepalopathy, a well-recognized ethanol-related adult syndrome involving neurodegenerative changes in the thalamus, midbrain, and brain stem, is believed to be due to thiamine deficiency that typically accompanies heavy chronic ethanol intake. Several lines of evidence suggest that ethanol can cause neurodegenerative changes in other regions of the adult brain by other mechanisms, but the nature of the other mechanisms remains largely a matter of speculation. Promising for its explanatory potential is a hypothesis involving the same transmitter systems (NMDA and GABA) that have been implicated in FAS. It is known that drugs that block NMDA receptors trigger a disinhibition syndrome in the adult brain that can injure or kill neurons by an excitotoxic mechanism (as opposed to the apoptotic mechanism operative during development). It is also known that drugs that activate GABAA receptors reverse this disinhibition syndrome and prevent it from injuring neurons in the adult brain. Thus, in the adult brain ethanol has neurotoxic potential because of its NMDA blocking property, but it is prevented from expressing neurotoxicity by its GABAA activating property. Recent evidence supports this concept and suggests that the protective mechanism is more than adequate to prevent expression of ethanol's neurotoxic potential in circumstances of acute heavy intake or intermittent chronic intake, but the protective mechanism may weaken and be overcome under conditions of heavy, steady chronic intake.

This proposed concept is appealing because it can readily explain the historical reality that ethanol has been used by human adults throughout the world for many centuries without apparent harm to most users, but with a subpopulation of chronic heavy abusers developing alcoholic hallucinosis and/or an irreversible neurodegenerative dementia syndrome. The other notable aspect of this historical reality is that because adult society has tended to perceive ethanol as user-friendly, countless human fetuses have been exposed in utero by mothers who were unaware that ethanol can act in the fetal brain by a dual neurotoxic mechanism (and no counteractive protective mechanism) to drive millions of neurons to commit suicide—neurons that would otherwise have developed normally and made a positive contribution to the brain's intellectual potential. Deletion of these neurons from the developing brain results in a variety of neurobehavioral disturbances, ranging from hyperactivity/attention deficit and learning disorders in childhood to major depressive and psychotic disturbances in adulthood.

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