Adolescent ethanol impacts brain immediate early gene expression, and peripheral neuroimmune, neuroendocrine, and behavioral responsivity to an adult ethanol challenge (2023)
Undergraduate: Aldrin Mosqueda
Faculty Advisor: Fulton Crews
Department: Bowles Center for Alcohol Studies, School of Medicine
While binge drinking (4-5+ drinks/2 hours) is prevalent in adolescence, preclinical models of human adolescent binge drinking (adolescent intermittent ethanol exposure; AIE) have revealed that there are long-term consequences on neural, immune, and endocrine systems. We hypothesized AIE will (1) exacerbate peripheral endocrine and immune responsivity to an adult ethanol challenge after abstinence, (2) will attenuate hippocampal immediate early gene expression, and (3) increase behavioral and physiological tolerance to ethanol relative to controls. Wistar rats were treated with either 5g/kg/day ethanol or water, i.g., 2-days-on/2-days-off from postnatal days (PND) 25 – PND 54 followed by 1.5 months of abstinence until adulthood. Rats were then exposed to one of two different ethanol challenges. In one condition, rats were intubated with 4 g/kg ethanol or water and then euthanized 90 minutes after the challenge, whereupon blood was collected for peripheral endocrine and immune markers (high mobility group box 1, HMGB1, and corticosterone, CORT), and brains were collected for immediate early gene expression (activity regulated cytoskeletal associated protein, Arc). A second cohort of rats received escalating intraperitoneal injections of ethanol whereupon they were assessed for intoxication indices and body temperature. Results indicate that while an adult ethanol challenge decreases Arc+immunoreactivity (+IR) in the dorsal hippocampal dentate gyrus in control-treated male rats, AIE-treated male rats did not exhibit ethanol-induced reductions in Arc+IR. Similarly, the adult ethanol challenge increased plasma HMGB1 in control but not AIE-treated rats. These findings were paralleled by behavioral changes in ethanol tolerance, where AIE-treated rats exhibit lower intoxication scores coupled with blunted hypothermic responses relative to adult controls. Conversely, CORT was similarly increased following an ethanol challenge in both AIE and CON male rats, suggesting AIE alters neural and immune but not endocrine responsivity to a later ethanol challenge in adulthood. Collectively, these findings suggest that AIE, induces behavioral, physiological, peripheral immune, and hippocampal neuronal tolerance even after months of abstinence. Supported by the Neurobiology of Adolescent Binge Drinking in Adulthood (NADIA) consortium of the NIAAA (U24 AA020024, U01 AA020023) and the Bowles Center for Alcohol Studies (P60 AA011605), K01 AA025713 (RPV), and K99 AA030089 (VMP)
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