ly, microglial dysfunction has been discovered to contribute to obsessive-compulsive behaviors (Greer and Capecchi 2002), consistent with microglia contributing to the neurobiology of addiction. Thus, microglia are sensitive to addictive drugs and stress, that lead to progressive adaptation that could alter neurobiology and behavior through innate immune gene induction.
Stress, ethanol, other addictive drugs, as well as sensory and hormonal signals, activate an oxidation sensitive transcription factor, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), that is highly expressed in monocytes and microglia. Monocytes and microglia express high levels of the transcription factor NF-κB as well as low levels of innate immune genes under normal conditions. Although NF-κB is found in most cells, it is the key transcription factor involved in induction of innate immune genes in microglia and other monocyte-like cells. Stimuli such as stress, cytokines, oxidative free radicals, ultraviolet irradiation, bacterial or viral antigens, and many other signaling molecules increase NF-κB-DNA binding and transcription of many genes particularly chemokines, cytokines, oxidases and proteases (Fig. 2). We find that ethanol increases NF-κB–DNA binding in brain in-vivo (Crews et al. 2006) or in-vitro in hippocampal-entorhinal cortex (HEC) brain slice 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.
Activation of the NF-κB spreads through positive loops (Fig. 2) increasing activation within and across glia and neurons (Zou and Crews 2010). Autocrine signaling involves secretion of signaling molecules that act on the same cells receptors to amplify activation of that cell, whereas paracrine signaling involves release of signals that activate cells nearby spreading the signal across cells. For example, reactive oxygen species (ROS) can increase NF-κB transcription of TNFα and TACE, the TNFα activating protease, as well as the TNFR1 receptor. Released TNFα stimulates NF-κB transcription through TNFR1 amplifying the signal in that cell and adjacent cells promoting TNFα induction (Fig. 2). Stress and drugs acutely signal through brain NF-κB. For example, restraint stress in rats induces brain NF-κB target genes TACE and TNFα mRNA within 30 minutes, and free mature brain TNFα within 1 hour (Madrigal et al. 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, inc