Neuroimmune signaling also regulates alcohol drinking behavior. Genetic comparisons among different strains of rats and mice found that addiction-like drinking behavior was associated with increased levels or activity of NF-κB, its regulatory proteins, and multiple innate immune genes (Mulligan et al. 2006). Furthermore, induction of innate immune genes resulted in increased ethanol consumption, whereas inactivation of such genes reduced drinking behavior (Blednov et al. 2005, 2011b). Thus, across genetically divergent strains of mice, innate immune responses to LPS corresponded to increases in ethanol consumption (Blednov et al. 2005, 2011b). In fact, even a single injection of LPS was able to produce a long-lasting increase in ethanol consumption (Blednov et al. 2011a) that corresponded to sustained increases in brain innate immune gene expression (Qin et al. 2007). These studies identified several innate immune molecules (e.g., β2-microglobulin, cathepsins, and CD14, a key innate immune signaling protein) as important for regulating drinking behavior. Thus, innate immune gene induction may underlie the progressive loss of behavioral flexibility, increasing negative affect, and increased alcohol drinking associated with repeat episodes of alcohol abuse and alcoholism.
