Sex differences in the behavioral sequelae of chronic ethanol exposure

Abstract

Rates of alcohol use disorders (AUDs) differ between men and women, and there is also marked variation between sexes in the effects of acute and chronic alcohol. In parallel to observations in humans, prior studies in rodents have described male/female differences across a range of ethanol-related behaviors, including ethanol drinking. Nonetheless, there remain gaps in our knowledge of the role of sex in moderating the effects of ethanol, particularly in models of chronic ethanol exposure. The goal of the current study was to assess various behavioral sequelae of exposing female C57BL/6J mice to chronic intermittent ethanol (CIE) via ethanol vapors. Following four weeks of CIE exposure, adult male and female mice were compared for ethanol drinking in a two-bottle paradigm, for sensitivity to acute ethanol intoxication (via loss of righting reflex [LORR]) and for anxiety-like behaviors in the novelty-suppressed feeding and marble burying assays. Next, adult and adolescent females were tested on two different two-bottle drinking preparations (fixed or escalating ethanol concentration) after CIE. Results showed that males and females exhibited significantly blunted ethanol-induced LORR following CIE, whereas only males showed increased anxiety-like behavior after CIE. Increased ethanol drinking after CIE was also specific to males, but high baseline drinking in females may have occluded detection of a CIE-induced effect. The failure to observe elevated drinking in females in response to CIE was also seen in females exposed to CIE during adolescence, regardless of whether a fixed or escalating ethanol-concentration two-bottle procedure was employed. Collectively, these data add to the literature on sex differences in ethanol-related behaviors and provide a foundation for future studies examining how the neural consequences of CIE might differ between males and females.

Chronic inflammatory pain drives alcohol drinking in a sex-dependent manner for C57BL/6J mice

“…Moreover, our female drinking data matches the maximal average consumption values previously reported in C57BL/6J mice undergoing continuous access to ≥ 10% alcohol (Jury et al, 2017; Middaugh et al, 1999; Smith et al, 2015). With such high baseline alcohol consumption, it is possible that saline-treated females have already reached maximal drinking in our study, so the addition of pain would not increase drinking in females.…”

“…Male CFA-treated mice consumed more alcohol and exhibited higher preference for the drug than saline-treated controls, while female CFA-treated mice only showed greater water intake than controls. Characteristic of C57BL/6J mice with continuous access to high concentrations of alcohol (Jury et al, 2017; Middaugh et al, 1999; Smith et al, 2015), drinking levels differed between sexes, with female mice exhibiting greater EtOH consumption and preference than male mice, regardless of saline or CFA treatment. These findings suggest that chronic inflammatory pain increases alcohol drinking in males, despite higher overall drinking in females.…”

Chemogenetic stimulation of mouse central amygdala corticotropin-releasing factor neurons: Effects on cellular and behavioral correlates of alcohol dependence

“…However, negative affect can be captured in alcohol-withdrawn mice using alternative assays. Most relevant to the present study, C57BL/6J males display increased digging activity and exacerbated hyponeophagia, but unaltered lightdark box exploration and social interaction, when tested 3-10 days into withdrawal from CIE [8,41,[55][56][57]. The latter data are consistent with our observation that chemogenetic stimulation of CeA CRF neurons in mice exacerbates hyponeophagia and tends to increase digging activity but has no effect in the EPM and social approach tests.…”

“…Our study shows that chemogenetic stimulation of mouse CeA CRF neurons increases GABA release onto medial CeA neurons and exacerbates hyponeophagia but does not affect voluntary alcohol consumption. These findings indicate that hyperactivity of CeA CRF neurons may contribute to elevated CeA GABA levels and anxiety-like behavior in CIE-exposed mice [8,[39][40][41] but is not sufficient to drive ethanol intake escalation.…”

Chronic inflammatory pain drives alcohol drinking in a sex-dependent manner

“…Male CFA-treated mice consumed more alcohol and exhibited higher preference for the drug than saline-treated controls, while female CFA-treated mice only showed greater total fluid intake than controls. Characteristic of C57BL/6J mice with continuous access to high concentrations of alcohol (Jury et al, 2017;Middaugh et al, 1999;Smith et al, 2015), drinking levels differed between sexes, with female mice exhibiting greater EtOH consumption, EtOH preference ratio, and total fluid intake than male mice, regardless of saline or CFA treatment. These findings suggest that chronic inflammatory pain increases alcohol drinking in males, despite higher overall drinking in females.…”