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 implicated in ethanol-induced neuroimmune signaling, as chronic ethanol consumption increases Tlr3 mRNA and components of the TRIF-dependent pathway (mRNA and protein) in the PFC and NAc, compared with decreases in the amygdala 24 h after ethanol removal (McCarthy et al., 2017c). Furthermore, de-creased activation of the TLR3-TRIF pathway by the IKKε/TBK1 inhibitor, amlexanox, reduces ethanol consumption (McCarthy et al., 2017c). Some evidence suggests that activation of the TLR3-TRIF pathway by chronic ethanol exposure increases neuroinflammation and neurodegeneration (Qin and Crews, 2012b). Initial findings in preclinical models suggest that TLR2, TLR3, and other mediators appear to be relevant targets for reducing ethanol consumption. Table 1 provides an overview of the pharmacological and genetic preclinical work demonstrating the involvement of TLR signaling in ethanol-related behaviors.
