UC San Diego

Alcohol use disorder (AUD) affects millions of people around the world and kills many, therefore, it is considered a serious public health issue. AUD is an economic burden, causes brain damage, and causes dysfunction of heart, liver, lungs, and kidney. Currently there are a few FDA approved medications and mutual help groups to combat AUD, but none are successful in preventing relapse over long-term. Therefore, there is need for novel therapeutics to treat AUD. Previous studies suggested that in animal models of AUD, animals with moderate to severe AUD had higher ethanol seeking behavior during abstinence that correlated with enhanced expression of platelet endothelial cell adhesion molecule (PECAM-1, a marker for angiogenesis), increased blood brain barrier leakage, and altered neuronal activation in medial prefrontal cortex (mPFC), a brain region implicated in relapse to ethanol seeking behaviors. However, it was unclear how microglia, a cell type known to regulate neuroimmune responses was altered during abstinence. Observations from our lab show that endostatin reduces the expression of PECAM-1, prevents gliosis that occurs during abstinence, and decreased ethanol seeking behavior during relapse. Postmortem tissue analysis using quantitative immunohistochemistry in the mPFC demonstrated that ethanol seeking correlated with microglial activation in the mPFC and endostatin reduced ethanol seeking and concurrently reduced microglial activation. Microglial deactivation was quantified using stereological methods and 3D structural analysis by investigating changes in soma to tip distance, cell soma area, total dendritic length, and number of intersections relative to distance from soma in microglial cells labeled with Iba-1. Phenotypic analysis revealed that the number of intersections relative to the distance from the soma recovered to normal levels after treatment with endostatin in alcohol dependent rats; which indicates a deactivation of microglia. Our research showed that endostatin can indirectly deactivate microglia and alter the neuronal response. Our research provides a possible mechanism of action to limit ethanol seeking behavior by indirectly deactivating microglia in the mPFC.