d embryonically and migrate to fetal brain early in development creating a unique self-renewing monocyte-like cell that is maintained by self-renewal. Microglia and vascular monocyte-macrophages are the primary innate immune cells in brain (Ransohoff and Cardona 2010). Healthy brain contains ramified “resting” microglia known to survey brain and regulate synapses (Graeber 2010). Microglia have a low threshold of activation with initial states secreting signaling molecules, increasing expression of Major Histocompatibility Complex (MHC) proteins and Toll-like receptor proteins (TLR), key proteins involved in innate immune amplification. Morphological activation states show cellular enlargement, increased cell matrix and adhesion protein expression and progressive induction of other specific genes. Efforts to establish subtypes of microglia have designated M1 and M2 states as proinflammatory and trophic respectively, although additional subtypes continually emerge (Colton and Wilcock 2010). Activated enlarged morphology is often associated with secretion of chemokines regulating cellular movement, particularly to sites of tissue damage, that progress to proinflammatory-oxidative activation that includes protease secretion. Highly activated microglia progress to mitosis, proliferation and phagocyte oxidative bursts that oxidize and engulf waste (Graeber 2010). “Amoeboid” phagocytic rounded macrophage-like cell morphology is common in neurodegenerative diseases and senescence (Colton and Wilcock 2010). Microglia can also initiate trophic and other signals needed for healing (Crews et al. 2006). Microglia are important components of brain that regulate brain function in complex ways not fully understood. Emerging studies suggest brain suppress microglial activation promoting a trophic “resting” state (Liu et al.). Stress, ethanol, other addictive drugs as well as sensory and hormonal signals activate monocytes and microglia. Cycles of stimuli lead to microglial adaptive conditioning (Shpargel et al. 2008). Interestingly, 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). Stres