Figure 1. The epigenetic allostasis model of the dark side of alcohol addiction.

The epigenome is dynamically altered by acute alcohol, chronic alcohol, and alcohol withdrawal in the amygdala and is crucial for the progression from casual use to addiction. Acute alcohol exposure opens the chromatin by inhibiting histone deacetylases (HDACs), thereby increasing histone acetylation around crucial synaptic plasticity-related genes such as brain-derived neurotrohic factor (Bdnf), activity regulated cytoskeleton-associated protein (Arc), and neuropeptide Y (Npy) in the amygdala, leading to anxiolysis. However, these biological parameters normalize (=) with continued alcohol exposure. During ethanol withdrawal, HDAC activity is increased leading to condensed chromatin structure and decreased expression of these genes as well as dendritic spine density. As the amygdala controls negative affective states, amygdalar chromatin conformation is critical for the development of anxiety seen in ethanol-withdrawn animals. Additionally, the condensed chromatin state is associated with greater ethanol preference and self-administration, ostensibly to relieve the negative affective states experienced. This switch from consuming alcohol for its pro-social, anxiolytic effects to drinking as a means to relieve negative affective states is critical to the addiction cycle and is reflected in the underlying epigenome of the amygdala ( Krishnan et al., 2014; Pandey et al., 2008a, b; Sakharkar et al., 2012; You et al., 2014).