It has been proposed that, instead of simply being a side effect of excessive alcohol consumption, neuronal damage associated with drinking actually may underlie some of the mechanisms of developing alcohol use disorder (Crews and Boettiger 2009). The development of dependence is thought to result at least in part from a lack of inhibition of the subcortical mesolimbic reward system by the frontal cortex (Koob and Le Moal 1997). Alcohol-induced cell death in regions such as the prefrontal cortex may lead to lack of inhibition in subcortical reward areas such as the striatum, which in turn may reduce behavioral inhibition and increase motivation to drink. Repeated stimulation of the innate immune system during chronic or heavy alcohol consumption may facilitate this process, leading to decreased inhibition of the mesolimbic reward system and thus increased drinking (Crews et al. 2011). These processes may be particularly relevant in adolescence, when persistent and long-lasting increases in brain neuroimmune-gene expression and neurodegeneration may be associated with the development of alcohol use disorder.
