Rationale <p>Binge drinking during adolescence is associated with a higher risk of developing Alcohol Use Disorders and impaired stress reactivity in adulthood. The hypothalamic-pituitary-adrenal axis matures during adolescence and is under strict GABAergic control. Yet, how early binge drinking alters GABAergic signaling in this region, and whether these changes contribute to later-life disruptions in stress reactivity, remain unknown.</p> Objectives <p>Our goal with these set of experiments was to test the hypothesis that adolescent binge drinking would impair maturation of GABAergic signaling in the paraventricular nucleus (PVN) and lead to aberrant behavioral and neuroendocrine stress reactivity.</p> Methods <p>Adolescent male and female C57BL/6J mice were given access to 20% ethanol or tap water under Drinking in the Dark-Multiple Scheduled Access paradigm from PD28 to PD42 and went through abstinence until adulthood. At adulthood (PD60+), the behavioral and endocrine response to two stressors, forced swim stress and social defeat stress, were evaluated.</p> Results <p>Only females with a history of adolescent drinking showed abnormal behavioral reactivity to stress, with increased immobility in the forced swim stressor task. Females with a history of adolescent binge drinking displayed a hypo-corticosterone response after social stress and males showed delayed negative feedback to the forced swim stressor. PVN-enriched tissue from these mice showed no changes in transcription of <i>Gabrg2</i>, but males showed a significant increase in expression of <i>Slc12a5</i>, which encodes for the chloride potassium co-transporter, KCC2. These males showed no change in KCC2 protein when evaluated by immunohistochemistry.</p> Conclusions <p>Taken together, these data show that adolescent binge drinking in pair-housed mice is associated with male-specific potential vulnerability in hypothalamic inhibitory signaling and disrupted adult stress reactivity in a sex- and stressor- dependent manner.</p>