Twelve TLRs have been identified in mice, with TLR4 being the most widely studied subtype for alcohol action (Crews et al., 2017). Other TLRs in brain are also implicated in alcohol’s neuroimmune effects. For example, TLR2 KO mice exhibit reduced ethanol consumption (Blednov et al., 2017). In addition, TLR2 may mediate ethanol-induced neuroinflammatory responses and anxiety-like behavior associated with ethanol withdrawal (Pascual et al., 2015). Ethanol promotes interactions between TLR2 and TLR4 (Fernandez-Lizarbe et al., 2013), suggesting it could simultaneously target both neuroimmune mediators. Adapter proteins, such as cluster of differentiation 14 (CD14), myeloid differentiation primary response 88 (MyD88), and TIR-domain-containing adapter-inducing interferon-β (TRIF), participate in several TLR pathways and genetic manipulation of these immune molecules regulates alcohol drinking. For example, Male and female CD14 KO mice drink less ethanol; however, male MyD88 KO mice increase binge-like ethanol consumption (Blednov et al., 2017). Pharmacological and brain-specific genetic inhibition of the inhibitor of NF-κB kinase subunit beta (IKKβ), which activates NF-κB signaling as part of the MyD88 pathway, decreases ethanol consumption in mice (Truitt et al., 2016). TLR3-TRIF-dependent signaling is also
