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 does not alter ethanol consumption in different drinking models (Harris et al., 2017). Moreover, lentiviral-mediated knockdown of Tlr4 expression in mouse NAc also fails to decrease ethanol consumption in different drinking procedures (Harris et al., 2017). In contrast with these findings, administration of siRNA for Tlr4 or Ccl2 into the central amygdala (CeA) or VTA in P rats reduces binge-like drinking (June et al., 2015). The opioid receptor antagonist nalmefene, which also inhibits TLR4 signaling, reduces ethanol-induced inflammation and binge-like drinking in female mice (Montesinos et al., 2017). Moreover, TLR4 blockade by (+)-naltrexone before or after ethanol exposure in adolescent mice reduces binge drinking in adulthood (Jacobsen et al., 2018a). Another recent study showed (+)-naltrexone decreases ethanol preference in mice, particularly during the dark cycle (Jacobsen et al., 2018b). There are some concerns over the use of (+)-naltrexone or (+)-naloxone to inhibit TLR4 signaling, as these compounds fail to inhibit LPS-induced TLR4 activation (Skolnick et al., 2014) and may have
