Targeting prefrontal cortex GABAergic microcircuits for the treatment of alcohol use disorder

Developing novel treatments for alcohol use disorders (AUDs) is of paramount importance for improving patient outcomes and alleviating the suffering related to the disease. A better understanding of the molecular and neurocircuit mechanisms through which alcohol alters brain function will be instrumental in the rational development of new efficacious treatments. Clinical studies have consistently associated the prefrontal cortex (PFC) function with symptoms of AUDs. Population-level analyses have linked the PFC structure and function with heavy drinking and/or AUD diagnosis. Thus, targeting specific PFC cell types and neural circuits holds promise for the development of new treatments. Here, we overview the tremendous diversity in the form and function of inhibitory neuron subtypes within PFC and describe their therapeutic potential. We then summarize AUD population genetics studies, clinical neurophysiology findings, and translational neuroscience discoveries. This study collectively suggests that changes in fast transmission through PFC inhibitory microcircuits are a central component of the neurobiological effects of ethanol and the core symptoms of AUDs. Finally, we submit that there is a significant and timely need to examine sex as a biological variable and human postmortem brain tissue to maximize the efforts in translating findings to new clinical treatments.