UC San Diego

Alcohol use disorder, or AUD, is a brain disorder that affects millions of people with fewFDA approved effective treatments at reducing relapse, with none preventing relapse episodes. Therefore, more research is necessary in order to find a targetable biochemical pathway for therapeutics to treat AUD and prevent relapse in alcoholics. Recent data in rodent models of moderate to severe AUD has demonstrated a correlation between higher levels of ethanol seeking behavior and increased levels of PECAM-1 in the prefrontal cortex of the brain, a region implicated in relapse to alcohol seeking. More notable is that increases in PECAM-1 is associated with blood-brain barrier (BBB) leakage, suggesting endothelial cell damage in relapsing alcoholics. Furthermore, published work from rodent studies and human postmortem tissue analysis have indicated severe neuroimmune responses in the brain that is correlated with increased relapse to drinking behavior. However, it remains unclear whether the activation state of microglia, a major player in the neuroimmune response that occurs due to alcohol metabolism, is associated with BBB leakage and endothelial cell damage in the prefrontal cortex. It was hypothesized that endostatin, an angiogenic inhibitor, would inhibit PECAM-1 and thus decrease BBB leakage. This was expected to reduce the peripheral neuroimmune response and prevent alteration in microglial activation. In order to test this, the brain tissue of male rats with moderate to severe AUD were analyzed. Specifically, quantitative immunohistochemistry and stereological cell analysis were used to evaluate microglial activation which was positively correlated to ethanol seeking behavior from the additional behavioral studies that were performed. It was found that endostatin reduced PECAM-1 expression in the prefrontal cortex, however, did not decrease ethanol seeking behavior of male rats. Additionally, microglial activation remained similar to the rats that were not treated with endostatin. Therefore, it is suggested that the peripheral immune response mediated by PECAM-1 is not directly linked to ethanol seeking behavior and microglial activation in the prefrontal cortex in male rats. From this, a new study investigating the internal neuroinflammation or immune response could help determine the mechanism to decrease microglial activation and thus lower relapse. This would be a significant advance in the effort to create an effective therapeutic for AUD.