GABAergic mechanisms in alcohol dependence.

The target of alcohol's effect on the central nervous system has been sought for more than 50 years in the brain's GABA system. The behavioral and emotional effects of alcohol in humans and rodents are very similar to those of barbiturates and benzodiazepines, and GABA_A receptors have been shown to be one of the sites of alcohol action. The mechanisms of GABAergic inhibition have been a hotspot of research but have turned out to be complex and controversial. Genetics support the involvement of some GABA_A receptor subunits in the development of alcohol dependence and in alcohol use disorders (AUD). Since the effect of alcohol on the GABA_A system resembles that of a GABAergic positive modulator, it may be possible to develop GABAergic drug treatments that could substitute for alcohol. The adaptation mechanisms of the GABA system and the plasticity of the brain are a big challenge for drug development: the drugs that act on GABA_A receptors developed so far also may cause adaptation and development of additional addiction. Human polymorphisms should be studied further to get insight about how they affect receptor function, expression or other factors to make reasonable predictions/hypotheses about what non-addictive interventions would help in alcohol dependence and AUD.