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 off-target/aversive effects, especially at higher doses (Tanda et al., 2016). Another study showed that (+)-naltrexone and (+)-naloxone do not inhibit TLR4-mediated NFκB activation, but rather act as TRIF-IRF3 antagonists (Wang et al., 2016). The experimental TLR4 inhibitor T5342126 de-creased ethanol consumption in both dependent and non-dependent mice, but also decreased locomotor activity, saccharin intake, and body temperature, indicating several non-specific effects (Bajo et al., 2016). Based on the current literature, the role of TLR4 in regulating alcohol consumption depends on the animal model, age, sex, drinking test, and genetic or pharmacologic manipulation used (Pascual et al., 2018). Overall, TLR4 alone does not seem to be critical for regulating drinking and likely works in concert with several other neuroimmune factors in brain to drive behavior.
