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 affect and depression-like behavior (Raison et al. 2009). Patients with major depression have increased blood proinflammatory markers and antidepressant therapy is associated with decreases in markers. In addition to increased innate immune gene expression, human depression involves structural changes in hippocampus with multiple studies finding hippocampal volume is decreased in patients with depression (Videbech and Ravnkilde 2004). Other studies have associated loss of hippocampal neurogenesis, the formation of new neurons, with depression and hippocampal shrinkage. Interestingly, antidepressants increase hippocampal neurogenesis in models of depression and increase humans hippocampal volume during reversal of depression (Dranovsky and Hen 2006). Stress, multiple addictive drugs, innate immune genes and other factors that precipitate depression, reduce hippocampal neurogenesis (Tanapat et al. 2001; Malberg and Duman 2003; Gregus et al. 2005). Factors that reduce neurogenesis increase depression-like behavior (Johnson et al. 2006). Activation of NF-κB is necessary for stress induced inhibition of neurogenesis and induction of depression-like behavior (Koo and Duman 2008) as well as social defeat models of depression (Christoffel et al. 2011). Further, antidepressant efficacy in rodent behavioral models requires hippocampal neurogenesis (Santarelli et al. 2003). In animal studies, endotoxin induced increases in innate immune genes reduce neurogenesis and increase depression-like behavior (Kelley 2011). TLRs are necessary components of both ethanol neurotoxicity (Alfonso-Loeches et al. 2010) and innate immune induced depressive behavior and reduction of neurogenesis (Kelley 2011). TLR, glutamate hyperexcitability and endogenous TLR agonists lead to persistent increases in brain hyperexcitability (Maroso et al. 2010). We have found that chronic ethanol increases brain innate immune genes, reduces brain neurogenesis and increases depression-like behavior (Stevenson et al. 2009) (Fig. 4.) Ethanol induced loss of neurogen