Regarding the mechanism of action of LPS to increase drinking, it appears to be mediated by toll-like receptors (TLR), because deletion of the CD14 adapter protein was sufficient to prevent such an increase of ethanol consumption. CD14 has been shown to be important in TLR4 as well as in TLR2 signaling (see Palsson-McDermott and O’Neill, 2004 for rev.) However, Naert et al. (2009) showed that TLR2 is not involved in the immune response to LPS. Therefore, TLR4-signaling is the most promising molecular mechanism for mediation of increase of alcohol consumption. There is evidence that peripherally injected LPS cannot permeate into the blood–brain barrier (Singh and Jiang, 2004). The peripheral cytokines released by LPS can signal the brain through a number of routes, including the activation of vagal afferent fibers projecting to the nucleus of the solitary tract and higher viscerosensory centers, cytokine-specific transport molecules expressed on the brain endothelium, and circumventricular organs (Besedovsky and del Rey, 1996; McAfoose and Baune, 2009; Quan, 2008). Upon reaching the brain, cytokine signals can be amplified through a central cytokine network that has profound
