Persistent changes of the HAT CBP activity and H4 acetylation were observed in the frontal cortex of C57BL/6 mice given 5-month chronic alcohol consumption followed by a 15-day withdrawal period (135). In that study, withdrawal-associated H4 hypoacetylation correlated with neuroinflammatory damage and the persistently altered memory and anxiety-related behaviors. Nonetheless, these changes were absent in mice lacking the Toll-like receptor 4 (TLR4) that have undergone the same treatment, suggesting a critical role for TLR4-mediated epigenetic modifications in mediating long-lasting deleterious effects of chronic alcohol on PFC-dependent behaviors (135). This is in line with findings in our laboratory showing a robust decrease in histone H4 acetylation in the medial PFC of C57/BL mice at 1 week after withdrawal from chronic alcohol consumption; this decrease was maintained for at least 6 weeks after alcohol withdrawal and correlated with the persistently impairment of working memory noted during abstinence (31, 47). Alcohol’s effects on H4 acetylation closely paralleled effects on CREB activation in the PFC. Further, systemic delivery of corticosterone inhibitor metyrapone or local intra-PFC blockade of MRs (via spironolactone) or GRs (via mifepristone)
