reased 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 associated with the transition from drug experimentation to addiction.
A number of studies suggest astrocytes and microglia are activated in addiction. Using both in vitro and in vivo models through a series of elegant studies Guerri's laboratory has clearly established that chronic ethanol treatment induces astroglial activation and astrogliosis in brain as indicated by marked upregulation of GFAP immunoreactivity within hypertrophic astrocytes, (Wilhelmsson et al. 2006; Chvatal et al. 2007; Gomez-Pinedo et al. 2008). TLR are pattern recognition receptors that activate NF-κB transcription. TLR and interleukin-1 receptors are expressed on microglia and other cells during innate immune activation contributing to amplification of signaling. Recently TLR4 was discovered to contribute to persistent innate immune gene induction and neurodegeneration by ethanol (Alfonso-Loeches et al. 2010). Guerri's studies indicate that chronic ethanol upregulation and activation of TLR4-MyD88-glial NF-κB signaling contributes to alcohol induced neurodegeneration. Acute alcohol activates TLR4 signaling to NF-κB as well as increasing expression of TLR4 (Alfonso-Loeches et al. 2010). These studies are consistent with ethanol induction of innate immune genes altering behavior and causing neurodegeneration related to addiction. Indomethacin, an anti-inflammatory drug, reduces chronic ethanol induction of brain innate immune genes, particularly in astrocytes, as well as neuronal markers of cell death and addiction-like behavioral dysfunction (Pascual et al. 2007) consistent with innate immune gene induction driving the neurobiology of addiction. Innate immune activation from oxidized phospholipids (Yang et al. 2010), and/or release of damage associated molecular pattern (DAMP) danger sensing molecules, such as high-mobility group box 1 (HMGB1) (Garg et al. 2010), that activate TLR and other signals are likely contributors to innate immune gene induction (Huang et al. 2010)(Fig. 2). Although loops of NF-κB activation are best established in models of alcoholism, all addictive drugs activate NF-κB transcription with the development of addiction (Russo et al. 2009; Loftis et al. 2010). These studies support innate immune gene induction in glia as important contributors to the neurobiology of addiction.
Anxiety and the bad feelings of negative affect are associated with increased drug craving as a key component of addiction (Breese et al. 2005; Koob and Volkow 2010). Breese' laboratory models addiction with repeated cycles of ethanol consumption and/or stress that progressively amplify anxiety and negative affect consistent with the cycles of stress and drug abuse known to promote addiction. Interestingly, brain injections of innate immune inducing molecules, e.g. the chemokine MCP-1, the cytokine TNFα, or the TLR4 agonist, lipopolysaccaride an innate immune inducer, progressively increase addiction-like anxiety substituting for an episode of stress or drug abuse (Breese et al. 2008). Cycles of stress and/or drug abuse cause progressive addiction-like anxiety and are known to induce innate immune genes in brain. The discovery that innate immune molecules injected into brain substitute for stress and/or drug abuse cycles promoting addiction-like anxiety, supports the role innate immune genes in driving the neurocircuitry and neuro