GABAAR α2-activated neuroimmune signal controls binge drinking and impulsivity through regulation of the CCL2/CX3CL1 balance

Background and Purpose Toll-like receptors (TLRs) are a family of innate immune system receptors that respond to pathogen-derived and tissue damage-related ligands and are increasingly recognized for their impact on homeostasis and its dysregulation in the nervous system. TLR signaling participates in brain injury and addiction, but its role in the alcohol-seeking behavior, which initiates alcohol drinking, is still poorly understood. In this review, we discuss our findings designed to elucidate the potential contribution of the activated TLR4 signal located in neurons, on impulsivity and the predisposition to initiate alcohol drinking (binge drinking). Results Our findings indicate that the TLR4 signal is innately activated in neurons from alcohol-preferring subjects, identifying a genetic contribution to the regulation of impulsivity and the alcohol-seeking propensity. Signal activation is through the non-canonical, previously unknown, binding of TLR4 to the alpha 2 subunit of the gamma-aminobutyric 2 acid A receptor (GABAAR alpha 2). Activation is sustained by the stress hormone corticotrophin-releasing factor (CRF) and additional still poorly recognized ligand/scaffold proteins. Focus is on the effect of TLR4 signal activation on the balance between pro- and anti-inflammatory chemokines [chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-X3-C motif) ligand 1 (CX3CL1)] and its effect on binge drinking. Conclusion The results are discussed within the context of current findings on the distinct activation and functions of TLR signals located in neurons, as opposed to immune cells. They indicate that the balance between pro- and anti-inflammatory TLR4 signaling plays a major role in binge drinking. These findings have major impact on future basic and translational research, including the development of potential therapeutic and preventative strategies.