 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 neurobiology that result in addiction-like behavior.
Opiates are known to be addicting drugs and have endogenous opiate receptors that contribute to the neurobiology of addiction (Koob and Volkow 2010). Opiate antagonists are used to treat both alcohol and opiate addiction. Interestingly, opiate antagonists block innate immune gene induction through a different novel mechanism that might contribute to the reversal of addiction-like behavior. LPS, endotoxin, induces large innate immune responses that are blocked by opiate antagonists (Liu et al. 2000) and protect dopamine neurons through inhibition of microglial innate immune activation and reduced NOX formation of ROS (Liu et al. 2000; Qin et al. 2005), independent of their opiate antagonist actions. Other studies find opiate antagonists block TLR4 activation of innate immune transcription, a site of action in innate immune loops (Fig. 2) (Gerald Frank 2011; Hutchinson 2011). Thus, opiate antagonist addiction therapy may be related to inhibition of innate immune responses.
Insight into the neurobiology of addiction can be gained from studies of post-mortem human brain. We found monocyte chemoattractant protein 1 (MCP-1, CCL2), a key innate immune chemokine, increased several fold in multiple regions of post-mortem alcoholic brain compared to age matched moderate drinking controls (Fig. 3) (He and Crews 2008). MCP-1 protein levels from alcoholic and control human brains indicated increased MCP-1 in ventral tegmental area (VTA), substantia nigra (SN), hippocampus and amygdala of alcoholic brains. We also found increased levels of microglial markers across alcoholic brain (He and Crews 2008). Chronic alcohol treatment of mice causes a similar persistent increase in brain MCP-1 (Fig. 3) (Qin et al. 2008). Interestingly, ethanol treatment of rat hippocampal brain slice cultures also increase MCP-1 and other innate immune genes (Fig. 3) (Zou and Crews 2010). These studies indicate that ethanol induces MCP-1 in rats and mice creating neurobiological changes found in human ad