Distinct transcriptional signatures in the adolescent hippocampus compared to adults: Interactions between alcohol and glucocorticoids.

Adolescent binge drinking is associated with long-lasting adverse consequences. Preclinical studies have shown that the adolescent neuroimmune system may be functionally immature, as adolescent rats show a blunted cytokine response to a variety of challenges, including ethanol. The neuroimmune gene expression alterations seen after acute ethanol mirror those produced by the glucocorticoid receptor (GR) agonist dexamethasone (DEX), providing evidence that rapid, ethanol-induced changes in neuroimmune gene expression are mediated by corticosterone (CORT) release and subsequent GR activation. Therefore, the present studies examined the impacts of age and history of adolescent intermittent ethanol exposure (AIE) on the relationship between hypothalamic-pituitary-adrenal (HPA) axis-mediated regulation of neuroimmune function and ethanol. Specifically, Experiment 1 assessed the transcriptomic response to acute ethanol (3.5 g/kg, i.p.) using RNA sequencing in adolescent and adult male rats. Experiment 2 tested age differences in neuroimmune gene expression following DEX (500 μg/kg, s.c.) in both sexes. Experiment 3 evaluated effects of AIE on neuroimmune gene expression to a DEX (500 μg/kg, s.c.) challenge in both males and females in adulthood. Although acute ethanol enriched vascular and neuroimmune-related pathways at both ages, adolescents and adults exhibited distinct transcriptomic responses, highlighting developmental differences in ethanol sensitivity. DEX elevated expression of IκBα and IL-6 and suppressed IL-1β and TNFα, with adolescents displaying blunted IL-6 induction relative to adults. Although AIE did not affect glucocorticoid-mediated neuroimmune responses to ethanol, the present findings support the existence of functional immaturity of the adolescent neuroimmune system that may increase vulnerability to persistent ethanol-induced alterations.