A major component of alcohol-induced neuroimmune activation is increased expression of cytokines, including IL-1β, TNF-α, IL-6, and CCL2 in brain (Lippai et al., 2013). IL-1 receptor (IL-1R) blockade, which attenuates ethanol-induced inflammasome activation and neuroinflammation (Lippai et al., 2013), reduces acute ethanol-induced sedation, protects mice from ethanol-induced motor impairment, and decreases binge-like drinking (Marshall et al., 2016; Yue Wu et al., 2011). Deletion of either IL-1R or the endogenous antagonist IL-1Ra produces opposite effects on ethanol behaviors such as its acute sedative and withdrawal effects (Blednov et al., 2015). IL-1R KO does not alter drinking in two-bottle choice continuous or limited-access drinking tests, but IL-1Ra KO mice show decreased ethanol consumption in both drinking models (Blednov et al., 2012). Double KO mice (IL-1R KO and TNF1R KO) drink significantly less ethanol and exhibit less stress-induced ethanol consumption (Karlsson et al., 2017). Other interleukins also regulate drinking behavior. For example, ethanol consumption is reduced in male and female IL-6 KO mice (Blednov et al., 2012), and Il22ra2 shRNA in the NAc reduces ethanol consumption in female alcohol-preferring (P) rats (Franklin et al., 2015).
