A pervasive theory has been that TLR4 is a principal mediator of alcohol’s neuroimmune effects and the development of excessive drinking (Crews et al., 2017). However, several negative findings regarding its direct role in alcohol consumption necessitate the exploration of other immune receptors and molecules. Additional TLRs, including TLR2, TLR3, and TLR7, should be considered for their contribution in modulating alcohol-induced inflammation and behavioral effects. P2XRs are also demonstrating potential roles in neuroimmune activation by alcohol and other drugs of abuse. P2X7-targeted ligands for use in PET imaging (Fantoni et al., 2017; Territo et al., 2017) are currently being developed and validated and may prove useful as biomarkers of neuroinflammation in AUD. Many of the pharmacotherapies discussed here, such as PDE inhibitors, PPAR agonists, and glial modulators, show promise in regulating alcohol-related behavior and neuroinflammation, yet the precise mechanisms behind their efficacy remain unclear. A key question for future studies is whether these treatments target the brain, the peripheral immune system, or a combination of both to exert their behavioral effects. Studies utilizing global KO mice demonstrate numerous cytokines and
