Adolescent ethanol exposure reprograms HMGB1 responsivity to adult ethanol challenge in males

Adolescent intermittent ethanol (AIE)-a model of human adolescent binge drinking- produces lasting changes in ethanol responsivity, including increased adult ethanol consumption and behavioral tolerance. However, the neuroimmune and neuroplastic mechanisms underlying these adaptations are unclear. Therefore, we used a model of human adolescent binge drinking (AIE; 5 g/kg/day ethanol or water, i.g., 2-day on/2-day off cycle from postnatal day (PND) 25-54) to assess disruptions to immune, neuronal, and endocrine responsivity to an acute ethanol challenge (4 g/kg) in adulthood (PND 105-110) in male Wistar rats. Acute ethanol increased plasma HMGB1 in adult controls, whereas AIE blunted this response without altering baseline plasma HMGB1. In addition, AIE persistently elevated plasma ALT, indicating persistent hepatic injury. Ethanol-induced plasma corticosterone responses were intact, suggesting divergence in innate immune versus endocrine responses to a later ethanol challenge after AIE. In the brain, AIE produced region-specific alterations in HMGB1 immunoreactivity (IR), increasing HMGB1+IR in the dentate gyrus but reducing it in CA3 and CA1. An acute ethanol challenge decreased hippocampal HMGB1+IR in control animals only, suggesting AIE produces enduring tolerance to ethanol-induced HMGB1 cellular export in the hippocampal formation. AIE also increased cyclooxygenase-2 (COX-2)+IR in the dentate and basolateral amygdala (BLA), and HMGB1 and COX-2+IR correlated across subjects. In BLA, acute ethanol in adulthood increased COX-2 selectively in controls. Collectively, these data indicate that AIE produces enduring, region and molecular target-specific reprogramming of ethanol responsivity that differentially emerges across innate immune, neuronal, and endocrine domains.