cultures (Zou and Crews 2006). Our studies and others indicate that ethanol increases transcription of NF-κB target genes including the chemokine MCP-1 (CCL2), the proinflammatory cytokines, TNFα, IL-1β, and IL6, the proinflammatory oxidases, iNOS (Zou and Crews 2010), COX (Knapp and Crews 1999), NOX (Qin et al. 2008) and proteases TACE and tPA (Zou and Crews 2010) (Fig. 2). Similarly stress increases brain NF-κB activation (Madrigal et al. 2001), cytokines, prostaglandin E2 and COX-2 levels (Madrigal et al. 2003) in part due to reversal of acute glucocorticoid anti-inflammatory responses to pro-inflammatory NF-κB activation in frontal cortex (Munhoz et al. 2010). Stress and drug abuse cycles promote addiction and elevate glucocorticoids (Armario 2010), likely contributing to activation of brain NF-κB transcription of innate immune genes. Methamphetamine shows similar persistent innate immune activation to ethanol in mice and humans (Loftis et al. 2010). Thus, the synergy of stress-drug abuse cycles leading to progressive loss of behavioral control and addiction are consistent with persistent, progressive brain innate immune gene induction.
