dicted brain (Fig. 3). Similarly, human methamphetamine addicts and mice treated with methamphetamine show persistent increases in innate immune proteins (Loftis et al. 2010). Increased protein levels are also reflected by increased mRNA. Gene arrays following mRNA expression in post-mortem human alcoholic brain find increased NF-κB and target gene expression. Okvist (2007) found chronic alcoholic brain to contain increased NF-κB nuclear binding p50 subunits with 479 NF-κB target genes upregulated in the frontal cortex. Another post-mortem alcoholic human gene expression analysis (Liu et al. 2006) found increases in innate immune cell adhesion and extracellular membrane (ECM) components. Thus, studies of post-mortem human alcoholic brain are consistent with increased innate immune gene expression in addicted brain.
Genetics contribute to risk of addiction with alcoholism being the most studied and experimentally established addiction with a significant genetic risk. Genes explain about 50% of the risk of alcohol addiction (Schuckit 2009). Interestingly, polymorphisms of Cyp2E1, an enzyme that metabolizes ethanol is associated with risk for alcoholism (Webb et al. 2010). In vivo, Cyp2E1 is highly expressed in monocyte-like cells where ethanol is immediately sensed through osmotic and Cyp2E1 metabolism. Cyp2E1 metabolism of ethanol increases ROS that activate proinflammatory NF-κB responses (Cao et al. 2005) (Fig. 2). Other human studies have found a direct link of NF-κB p50 to alcohol dependence (Flatscher-Bader et al. 2005; Okvist et al. 2007;Taylor et al. 2008). Polymorphisms in the precursor gene (NF-κB 1) of the NF-κB p50 subunit associate with risk for alcoholism (Taylor et al. 2008). Alleles of TNFα that increase expression have been linked to alcoholism and alcoholic liver disease (Pastor et al. 2000; Powell et al. 2000; Pastor et al. 2005). Alleles of IL-10 have also been linked to alcoholism (Pastor et al. 2000). Interestingly, in both cases alleles associated with alcoholism increase pro-inflammatory responses, e.g. alleles associated with alcoholism increase pro-inflammatory cytokine TNFα and decrease anti-inflammatory IL-10 secretion. Similarly polymorphisms, to the Interleukin-1 receptor antagonist and multiple other alleles of the IL-1 gene complex are associated with risk for alcoholism (Saiz et al. 2009). Thus, gene polymorphisms that alter innate immune NF-κB and NF-κB target gene expression are associated with genetic risk for human alcoholism consistent with increased brain innate immune gene expression contributing to the neurobiology of addiction.
Innate immune gene expression is known to alter behavior. The most serious side effect of treatment of cancer patients with proinflammatory interferon and interleukin is severe depression that must be treated with antidepressants. Multiple other studies have linked negative affect and depression to innate immune activation (Kelley 2011). Bacterial endotoxin (LPS) an effective inducer of innate immune genes causes sickness behavior and negative affect across multiple species. In rodents, models of depression-like behavior are linked to innate immune activation and in healthy humans LPS infusions reduce reward responses and increase depressed mood (Eisenberger et al. 2010). Increased negative affect is an important component of the neurobiology of addiction (Koob and Volkow 2010).
Drug consumption is also linked to innate immune gene expression. Addictionlike drinking behavior in rats and mice associates with increased NF-κB, its regulatory proteins and innate immune genes (Mulligan et al. 2006). Interestingly, microglobulin (β2M) an NF-κB target gene involved in microglial MHC immune signaling (Pahl 1999) shows the largest increase in high alcohol preferring brain transcriptomes (Mulligan et al. 2006). Innate immune gene induction in multiple mouse studies finds induction suppression through transgenic knock outs associates with increased drinking or decreased drinking respectively across strains of mice. These studies further support the role of these genes 