We hypothesized that the normal functioning of the immune system maintains drinking at low to moderate levels, whereas activation of the neuroimmune system could promote excessive alcohol consumption. We tested this by using LPS to activate neuroimmune signaling before measuring drinking. LPS is a bacterial endotoxin normally confined to the gut, but it can leak from the gut as a result of chronic alcohol abuse (Mandrekar and Szabo, 2009). LPS produces activation of the immune system when administered systemically by binding to toll-like receptor 4 (TLR4) found on macrophages, Kupffer and stellate cells in the liver, and endothelial cells (Andonegui et al., 2003; Mandrekar and Szabo, 2009; Suzumura et al., 2006; Zanoni and Granucci, 2010). TLR4 is also found in the brain on neurons, astrocytes, microglia and endothelial cells (Tang et al., 2007; Mallard et al., 2009). Some publications suggest that LPS elicits TLR4 signaling in the brain by interactions with these receptors (Chakravarty and Herkenham, 2005; Gosselin and Rivest, 2008), but others have failed to find LPS within the brain parenchyma after systemic administration (Singh and Jiang, 2004). It
