In agreement with human studies, brain gene expression studies in animal models indicate a role for immune and microglial transcripts in mediating alcohol action. Chronic alcohol treatment in mice induced pro-inflammatory gene expression that persisted for at least one week of abstinence [24], while LPS-induced neuroimmune activation persisted for months [25]. LPS treatment in mice also produced a prolonged increase in alcohol drinking and preference [26]. Moreover, animals lacking specific innate immune genes showed reduced preference for drinking alcohol [2,3,27] as well as altered acute responses to the motor and sedative effects of alcohol [28*]. In a multivariate analysis of 37 different mutant mice chronically treated with alcohol using a two-bottle choice drinking paradigm, a highly correlated phenotypic cluster was identified, suggesting a role for genes involved in GABA (Gad2, Gabra1), glycine (Glra1), and neuroimmune signaling (Ccr2, Il6) [29].
