ponses, 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 in regulating excessive addiction like drug consumption (Blednov et al. 2005; Blednov 2010). A single injection of LPS is able to produce a long-lasting increase in alcohol consumption (Blednov 2011) that corresponds to persistent increases in brain innate immune gene expression (Qin et al. 2007). These findings are consistent with innate immune gene expression driving addiction like behavior, both excessive consumption and the negative-affect, anxiety and depression-like behaviors of addiction.
Emotion or affect have an impact on health with positive affect or happiness associating with health and negative affect, bad feeling with illness. Psychiatric affective disorders cover a range of negative affect elements including anger, anxiety, melancholia, depression, major depressive disorder and substance use disorder. Drug addiction cues include a visceral emotional “gut” reaction, often one of uneasiness until the habit is satisfied. A variety of studies suggest that the extended amygdale, a neuroanatomic circuit including the amygdale, hippocampus, bed nucleus of the stria terminalis and the nucleus accumbens integrate brain arousal–stress systems producing negative emotional states that promote the development of addiction (Koob and Volkow 2010). Mood and negative affect are reflected in the co-morbidity of addiction and depression. About half of individuals with a lifetime history of alcoholism also have depression (Miller et al. 1996; Schuckit et al. 1997) and reversal of depression and alcohol dependence are linked (Mueller et al. 1994; Greenfield et al. 1998). Progressive drug-induced negative affect and depression-like behaviors are important components of addiction (Koob and Volkow 2010). The overlapping findings of increased innate immune gene expression in addiction and depression are consistent with a common molecular mechanism of addiction induced depression and endogenous depression.
A significant body of evidence supports the hypothesis that innate immune gene induction in brain causes negative affec