TLR4 is thought to be a major contributor to ethanol-induced neuroimmune activation (Alfonso-Loeches et al., 2010; Crews et al., 2013; Crews and Vetreno, 2015; Fernandez-Lizarbe et al., 2009; Montesinos et al., 2016b) (Bajo et al., 2016; Lippai et al., 2013; Montesinos et al., 2016b; Rubio-Araiz et al., 2016). This prompted studies of its potential role in promoting alcohol consumption and other relevant behaviors. Although the TLR4 agonist LPS increases voluntary ethanol consumption in male and female mice (Blednov et al., 2011), this was surprisingly not observed in another study using C57BL/6J mice (Lainiola and Linden, 2017). Differences in experimental housing conditions may have contributed to the different results. In rats, LPS transiently decreases operant self-administration of ethanol, but this was possibly due to sickness-like behavior (Harris et al., 2017). Several studies report that genetic deletion of TLR4 does not alter ethanol consumption (Blednov et al., 2017; Harris et al., 2017; Pascual et al., 2011). Inhibition of TLR4 signaling using the mu-opioid inactive stereoisomer (+)-naloxone, which is a selective TLR4 inhibitor (Hutchinson et al., 2008a, 2008b; Wang et al., 2016), also
