Summary And Conclusions

Alcohol Free Forever

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Human and animal studies have clearly established that chronic alcohol intake causes a loss of brain mass as a result of ethanol-induced brain damage. Although human studies show loss of brain tissue and the loss of specific brain nuclei after years of alcohol consumption, recent animal studies have indicated that neuronal loss can occur after only a few days of binge drinking. The neuropathol-ogy in humans involves both gray and white matter, whereas the animal studies have focused on neuronal loss (e.g., gray matter). It is possible that long-term animal studies could confirm the human findings. Alcohol-induced neuropathology is associated with the loss of some cognitive functions, including the executive functions associated with the frontal cortex. Neuropathology and the loss of executive functions, including impulse inhibition and goal setting, could contribute to the development of alcohol dependence.

Ethanol-induced brain damage appears to be secondary to changes in glutamate and GABA transmission. Acute ethanol exposure inhibits NMDA receptors and reduces extracellular glutamate, which could reduce NMDA trophic signaling through tyrosine kinases. Chronic ethanol exposure leads to NMDA supersensitivity because of changes in the receptor response. Although some reports have found an increase in NMDA receptor number, more studies have shown supersensitive NMDA responses in the absence of more receptors. Nor do models of alcohol dependence show increased NMDA receptor density. This suggests that other mechanisms of NMDA supersensitivity are involved in this adaptive response to ethanol. The supersensitive NMDA response includes chronic ethanol-induced supersensitivity to NMDA excitotoxicity. NMDA supersensitivity combined with increased extracellular glutamate during ethanol withdrawal are likely contributors to ethanol neurotoxicity. Blunting of GABA inhibitory responses would be expected to enhance neurotoxicity, as would the loss of trophic signals. The loss of BDNF and other trophic signals during chronic ethanol treatment can sensitize cells to NMDA toxic insults. Thus, the combination of NMDA supersensitivity, increased extracellular glutamate, GABA blunting, and loss of trophic signals are likely factors in ethanol-induced neurotoxicity. Unique aspects of these factors in combination probably contribute to specific brain-region sensitivity. Although additional studies are needed to determine the exact role of brain-region-specific ethanol neurotoxicity and its relationship to the development of alcohol dependence, it is clear that glutamate plays a significant role in ethanol neurotoxicity.

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