Molecular and behavioral aspects of the actions of alcohol on the adult and developing brain.

The brain is one of the major target organs of alcohol actions. Alcohol abuse can lead to alterations in brain structure and functions and, in some cases, to neurodegeneration. Cognitive deficits and alcohol dependence are highly damaging consequences of alcohol abuse. Clinical and experimental studies have demonstrated that the developing brain is particularly vulnerable to alcohol, and that drinking during gestation can lead to a range of physical, learning and behavioral defects (fetal alcohol spectrum disorders), with the most dramatic presentation corresponding to fetal alcohol syndrome. Recent findings also indicate that adolescence is a stage of brain maturation and that heavy drinking at this stage can have a negative impact on brain structure and functions causing important short- and long-term cognitive and behavioral consequences. The effects of alcohol on the brain are not uniform; some brain areas or cell populations are more vulnerable than others. The prefrontal cortex, the hippocampus, the cerebellum, the white matter and glial cells are particularly susceptible to the effects of ethanol. The molecular actions of alcohol on the brain are complex and involve numerous mechanisms and signaling pathways. Some of the mechanisms involved are common for the adult brain and for the developing brain, while others depend on the developmental stage. During brain ontogeny, alcohol causes irreversible alterations to the brain structure. It also impairs several molecular, neurochemical and cellular events taking place during normal brain development, including alterations in both gene expression regulation and the molecules involved in cell-cell interactions, interference with the mitogenic and growth factor response, enhancement of free radical formation and derangements of glial cell functions. However, in both adult and adolescent brains, alcohol damages specific brain areas through mechanisms involving excitotoxicity, free radical formation and neuroinflammatory damage resulting from activation of the innate immune system mediated by TLR4 receptors. Alcohol also acts on specific membrane proteins, such as neurotransmitter receptors (e.g. NMDA, GABA-A), ion channels (e.g. L-type Ca²⁺ channels, GIRKs), and signaling pathways (e.g. PKA and PKC signaling). These effects might underlie the wide variety of behavioral effects induced by ethanol drinking. The neuroadaptive changes affecting neurotransmission systems which are more sensitive to the acute effects of alcohol occur after long-term alcohol consumption. Alcohol-induced maladaptations in the dopaminergic mesolimbic system, abnormal plastic changes in the reward-related brain areas and genetic and epigenetic factors may all contribute to alcohol reinforcement and alcohol addiction. This manuscript reviews the mechanisms by which ethanol impacts the adult and the developing brain, and causes both neural impairments and cognitive and behavioral dysfunctions. The identification and the understanding of the cellular and molecular mechanisms involved in ethanol toxicity might contribute to the development of treatments and/or therapeutic agents that could reduce or eliminate the deleterious effects of alcohol on the brain.