s 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, 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 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