2002). Similarly an acute dose of ethanol activates NF-κB in brain within 30 minutes (Ward et al. 1996). Although NF-κB is expressed in most cells, in brain NF-κB is transcriptionally active primarily in glia (Mao et al. 2009), although, confusion regarding neuronal NF-κB is commonly found in the literature (Massa et al. 2006). Activation of NF-κB acutely leads to paracrine and autocrine amplification during repeated drug abuse and/or stressful events that create loops of NF-κB activation amplifying innate immune gene induction (Fig. 2). The loops of NF-κB activation lead to persistent increases in oxidative free radicals from oxidases, increased TLR expression with increased formation of endogenous TRL agonists, and chemokine-cytokine receptor upregulation (Qin et al. 2008; Zou and Crews 2010). Ethanol and stress activate microglia to secrete NF-κB target genes leading to mild activated morphology with repeated cycles progressively increasing innate immune gene induction. Maximally activated phagocytic oxidative burst macrophage-like microglial activation occurs with severe neurodegeneration, but is rare in addiction without severe degeneration (He and Crews 2008; Qin et al. 2008). These studies indicate that repeated drug abuse and stress lead to loops of NF-κB transcription of innate immune genes that mimic the progressive and persistent changes in behavior
