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Importance of sex and trauma context on circulating cytokines and amygdalar GABAergic signaling in a comorbid model of posttraumatic stress and alcohol use disorders


Alcohol use disorder (AUD) and anxiety disorders are frequently comorbid and share mechanisms that could be therapeutic targets. To facilitate mechanistic studies, we adapted an inhibitory avoidance-based “2-hit” rat model of posttraumatic stress disorder (PTSD) and identified predictors and biomarkers of comorbid alcohol (ethanol)/PTSD-like symptoms in these animals. Stressed Wistar rats received a single footshock on two occasions. The first footshock occurred when rats crossed into the dark chamber of a shuttle box. Forty-eight hours later, rats received the second footshock in a familiar (FAM) or novel (NOV) context. Rats then received 4 weeks of two-bottle choice (2BC) ethanol access. During subsequent abstinence, PTSD-like behavior responses, GABAergic synaptic transmission in the central amygdala (CeA), and circulating cytokine levels were measured. FAM and NOV stress more effectively increased 2BC drinking in males and females, respectively. Stressed male rats, especially drinking-vulnerable individuals (≥0.8 g/kg average 2-h ethanol intake with >50% ethanol preference), showed higher fear overgeneralization in novel contexts, increased GABAergic transmission in the CeA, and a profile of increased G-CSF, GM-CSF, IL-13, IL-6, IL-17a, leptin, and IL-4 that discriminated between stress context (NOV > FAM > Control). However, drinking-resilient males showed the highest G-CSF, IL-13, and leptin levels. Stressed females showed increased acoustic startle and decreased sleep maintenance, indicative of hyperarousal, with increased CeA GABAergic transmission in NOV females. This paradigm promotes key features of PTSD, including hyperarousal, fear generalization, avoidance, and sleep disturbance, with comorbid ethanol intake, in a sex-specific fashion that approximates clinical comorbidities better than existing models, and identifies increased CeA GABAergic signaling and a distinct pro-hematopoietic, proinflammatory, and pro-atopic cytokine profile that may aid in treatment.

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Fig. 1: The “2-hit” stress paradigm increased ethanol intake in rats with intermittent, limited ethanol access.
Fig. 2: Effects of prior “2-hit” stress with familiar (FAM) vs. novel (NOV) context on anxiety-related behaviors during abstinence.
Fig. 3: Drinking-vulnerable males exhibit increased two-bottle choice (2BC) drinking with heightened fear overgeneralization.
Fig. 4: Stress increased central amygdala (CeA) inhibitory GABAergic transmission and elevated peripheral cytokines.


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We thank Drs Amanda J. Roberts for paradigm design advice and Sarah A. Laredo for help with figure art. This is manuscript number 29810 from The Scripps Research Institute.


Support for this study was provided by The National Institute on Alcohol Abuse and Alcoholism grants AA027700, AA013498, P60 AA006420, AA017447, AA021491, AA015566, K99 AA026638, and T32 AA007456, The National Institute on Drug Abuse grant R21 DA046865 as well as the Pearson Center for Alcoholism and Addiction Research.

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Steinman, M.Q., Kirson, D., Wolfe, S.A. et al. Importance of sex and trauma context on circulating cytokines and amygdalar GABAergic signaling in a comorbid model of posttraumatic stress and alcohol use disorders. Mol Psychiatry (2020).

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