Cues associated with repeated ethanol exposure facilitate the corticosterone response to ethanol and immunological challenges in adult male Sprague Dawley rats: implications for neuroimmune regulation.

Background: We previously found a conditioned increase in central neuroinflammatory markers (Interleukin 6; IL-6) following exposure to alcohol-associated cues. Recent studies suggest (unconditioned) induction of IL-6 is entirely dependent on ethanol-induced corticosterone. Objectives: The goals of these present studies were to test whether alcohol-paired cues facilitated the hypothalamic-pituitary-adrenal (HPA) axis response to either a subthreshold priming alcohol dose or an immune or psychological stress challenge Methods: In Experiment 1 ( N  = 64), adult male Sprague Dawley rats were trained (paired or unpaired, four pairings total) with  either vehicle or 2 g/kg alcohol [intragastric (i.g.) or intraperitoneal (i.p.)] injections. In Experiments 2 ( N  = 28) and 3 ( N  = 30), male rats were similarly trained but with 4 g/kg alcohol i.g. intubations. On test day, all rats were either administered a 0.5 g/kg alcohol dose (i.p. or i.g. Experiment 1), a 100 µg/kg i.p. lipopolysaccharide (LPS) challenge (Experiment 2), or a restraint challenge (Experiment 3), and exposed to alcohol-associated cues. Blood plasma was collected for analysis. Results: Alcohol-associated cues facilitated the plasma corticosterone response to a subthreshold dose of alcohol ( F 1,28  = 4.85, p  < .05) and an immune challenge ( F 8,80  = 6.23, p  < .001), but not a restraint challenge (F 2,27  = 0.18, p  > .05). Conclusion: These findings reveal that the impact of the cues associated with alcohol intoxication on the HPA axis may be context-specific. This work illustrates how HPA axis learning processes form in the early stages of alcohol use and has important implications for how the HPA and neuroimmune conditioning may develop in alcohol use disorder in humans and facilitate the response to a later immune challenge.