Project Summary/Abstract: Adolescent alcohol abuse remains a major public health problem. Beyond the immediate physical ramifications that alcohol use can have on health, there is growing focus on the long-lasting, negative effects of binge alcohol consumption in particular. Due at least in part to its significance as a period of neuronal refinement, adolescence is an epoch of distinct vulnerability to the neuropathological consequences of binge alcohol use. While many studies have examined changes in normal brain development, few have focused on alterations in blood brain barrier integrity. This proposal will examine the enduring consequences of binge-like adolescent ethanol exposure on blood brain barrier (BBB) function using a rodent model. We will determine the extent to which adolescent ethanol use can impair basal, adult BBB function and identify mechanisms that govern these changes. This work will expand upon prior research using an established model of adolescent chronic intermittent ethanol exposure (CIE) that produces sexually dimorphic changes in hypothalamic-pituitary- adrenal (HPA) axis function and cytokine gene expression that persist into adulthood. Using this model, adolescent CIE produced increases in brain ethanol concentrations resulting from adult ethanol challenge, suggesting increased access of small molecules (including drugs of abuse) into the central nervous system. Adult animals also display increased expression of vascular endothelial growth factor (VEGF) protein in response to ethanol exposure, providing a putative mechanism for BBB disruption. For these reasons, we hypothesize that adolescent CIE produces disruptions in normal BBB function that manifest as increased permeability in adulthood. We propose that increases in VEGF occurring across the cycles of intoxication and withdrawal produced by adolescent CIE create these changes. Two specific aims will delineate 1) the extent to which adolescent CIE produces BBB dysfunction in male and female Sprague-Dawley rats and 2) investigate the role of VEGF-A in producing these changes. This work will significantly change our understanding of how alterations in BBB permeability affect subsequent responses to future challenge as well as how developmental ethanol exposure changes the normal trajectory of BBB development.