Sex differences in traumatic stress reactivity in rats with and without a history of alcohol drinking

Abstract

Background: Alcohol misuse and post-traumatic stress disorder (PTSD) are highly comorbid, and treatment outcomes are worse in individuals with both conditions. Although more men report experiencing traumatic events than women, the lifetime prevalence of PTSD is twice as high in females. Despite these data trends in humans, preclinical studies of traumatic stress reactivity have been performed almost exclusively in male animals. Methods: This study was designed to examine sex differences in traumatic stress reactivity in alcohol-naive rats (experiment 1) and rats given intermittent access to 20% ethanol in a 2-bottle choice paradigm for 5 weeks (experiment 2). Animals were exposed to predator odor (bobcat urine) and tested for contextual avoidance 24 h later; unstressed controls were never exposed to predator odor. We evaluated changes in physiological arousal using the acoustic startle response (ASR) test at day 2 post-stress and anxiety-like behavior measured in the elevated plus-maze (EPM) at day 17 post-stress. In experiment 3, time course of corticosterone response was examined in male and female rats following exposure to predator odor stress. Results: Alcohol-naive males and females exposed to predator odor displayed blunted weight gain 24 h post-stress, but only a subset of stressed animals exhibited avoidance behavior. In alcohol-drinking animals, the proportion of avoiders was higher in males than females, and predator odor exposure increased ASR in males only. Stressed females exhibited blunted ASR relative to unstressed females and stressed males, regardless of alcohol drinking history. Alcohol-experienced females presented lower anxiety-like behavior and higher general activity in the EPM in comparison with alcohol-experienced males. Plasma corticosterone levels were higher in females immediately after predator odor exposure until 60 min post-stress relative to males. Conclusions: We report robust sex differences in behavioral and endocrine responses to bobcat urine exposure in adult Wistar rats. Also, males with a history of chronic moderate alcohol drinking exhibited increased traumatic stress reactivity relative to alcohol-drinking females. Our findings emphasize the importance of considering sex as a biological variable in the investigation of traumatic stress effects on physiology and behavior.

Housing Condition Differentially Impacts Escalation of Alcohol Intake, Relapse‐Like Drinking, Anxiety‐Like Behavior, and Stress History Effects by Sex

“…Scott and colleagues employed an access paradigm in which alcohol was provided for 3 contiguous days each week, followed by 4 days’ abstinence, resulting in 4 contained episodes of alcohol access across 4 weeks, yielding minimal escalation of intake, which may be comparable to our findings in pair‐housed females. It should be noted that escalation of intake over time and equivalent levels of intake to those reported here have been observed previously in solitary‐housed rats of both sexes (Schramm‐Sapyta et al, 2014), whereas pair‐housed males and females with a single alcohol source for both cage mates did not escalate intake visibly over 5 weeks’ IA2BC (Albrechet‐Souza et al, 2020). The lack of escalation in pair‐housed rats of both sexes sharing an alcohol source may be complicated by competition for the alcohol source and data representing intake by cage, rather than by individual animal.…”

“…It should be noted that ours is not the first study to display equivalent levels of drinking between male and female rodents. In fact, similar intake between the sexes has been demonstrated multiple times (e.g., Finn et al, 2018a;Fulenwider et al, 2019;Radke et al, 2019;Schramm-Sapyta et al, 2014), including for Wistars given intermittent alcohol access (Albrechet-Souza et al, 2020). The source of variability in drinking levels in general, and sex differences in particular, remains unknown.…”

A severe form of maternal separation in rat consisting of nineteen-day 6-hour daily separation at unpredictable times minimally affects behavior across lifespan and possibly confers protection against some maladaptive outcomes

“…In our study, there was no significant effect of MS on either basal or stress-induced serum corticosterone levels. However, as widely reported in the literature (Babb et al, 2013;Albrechet-Souza et al, 2020), we did observe a higher corticosterone peak response in female rats, correlating with the increased female struggling time observed in the FST.…”

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

“…Another consideration is that these studies were conducted in male rats only. Sex differences in response to predator odor are documented 63 and women suffer from PTSD at three times the rate of men 3,16 . Therefore, future work should examine sex differences in response to TMT stress.…”