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

ABSTRACT

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.

KEYWORDS:

• Corticosterone
• ethanol
• Pavlovian conditioning
• lipopolysaccharide
• restraint stress
• HPA axis

Acknowledgements

The authors would like to thank Drs. Michael Fanselow and Jeremy Trott for their input on earlier drafts of the paper.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/00952990.2023.2169831.

Additional information

Funding

Research reported in this publication was supported by the National Institute of Health Grants P50AA017823 (TD), T32AA025606 (ASV), and F31AA027959 (ASV), as well as the Center for Development and Behavioral Neuroscience at Binghamton University.Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the above stated funding agencies.