Chronic binge-drinking models repeatedly found that ethanol exposure increases the expression of a variety of neuroimmune genes in the brain and that these alterations may persist over long periods (see figure 1). For example, one study found that chronic ethanol exposure induced the neuroimmune gene cyclooxygenase 2 (COX2) in multiple cortical and limbic brain regions long after physical signs of withdrawal had subsided (Knapp and Crews 1999). However, ethanol did not induce COX2 in transgenic mice lacking TLR4, suggesting that this process involves TLR4 (Alfonso-Loeches et al. 2010). Chronic alcohol exposure also altered the activity of NF-κB and another regulatory protein, cyclic AMP-responsive element binding protein (CREB). Specifically, ethanol treatment of HEC brain slice cultures increased NF-κB binding to DNA probes modeling gene promoter regions and decreased CREB binding to DNA probes modeling CREB-responsive gene promoter DNA (Zou and Crews 2006).
