biology 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 addicted 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 res