Sex‐related differences in pattern of ethanol drinking under the intermittent‐access model and its impact on exploratory and anxiety‐like behavior in Long‐Evans rats

Abstract

Background While men in the United States consume more alcohol than women, rates of drinking are converging. Nevertheless, females remain underrepresented in preclinical alcohol research. Here, we examined rats' sex‐related differences in patterns of ethanol (EtOH) drinking and the effects of this drinking on exploratory and anxiety‐like behavior. Methods Adult male and female Long‐Evans rats were given 20% ethanol under the intermittent‐access two‐bottle‐choice paradigm. Their intake was measured daily for the first 7 weeks. During the eighth week, intake was measured over the 24 h of daily access. During the ninth week, they, along with EtOH‐naive controls, were tested prior to daily access in a novel chamber, light–dark box, and hole board apparatus. During the tenth week, blood ethanol concentration (BEC) was assessed after 30 to 40 min of access. Results Females overall demonstrated higher ethanol intake and preference across all access weeks than males, although only half of females drank significantly more than males. Across 24 h of daily access, both sexes had their highest intake in the first 30 min and their lowest in the middle of the light phase of the light/dark cycle. Despite their greater ethanol intake, females did not show significantly different BECs than males. In behavioral tests, females showed less vertical time in a novel activity chamber, more movement between chambers in a light–dark box, and more nose pokes in a hole‐board apparatus than males. While a history of ethanol drinking led to a trend for lower vertical time in the activity chamber and greater chamber entries in the light–dark box, the effects were not sex‐dependent. Conclusions These results suggest that female and male rats could both be tested for acute effects of ethanol after 30 min of daily access, but that nuanced considerations are needed in the design of these experiments and the interpretation of their findings.

Genetics and epigenetics: paternal adolescent ethanol consumption in serotonin transporter knock-out rats and offspring sensitivity to ethanol

“…These findings are in mostly line with previous research showing sex differences in drug use, particularly stimulant drugs (Carroll and Anker 2010). Females have higher alcohol preference ratios (alcohol/total fluid) in free choice paradigms (Lancaster and Spiegel 1992;Priddy et al 2017;Pirino et al 2022), wider distribution of alcohol consumption across the day (Juárez and Tomasi 1999), and higher intake of alcohol per body weight (Lancaster et al 1996;Klein 2015). Other studies show that female mice and rats acquire ethanol self-administration faster (Melón et al 2013;Moore and Lynch 2015), show less withdrawal symptoms (Varlinskaya and Spear 2004), and have a lower response to pharmacological treatments for AUD (Moore and Lynch 2015) compared to males.…”

“…Female animals performed better than males. Bars denote standard error same ethanol dose injection (Mankes et al 1991) and similar blood ethanol concentrations for greater ethanol intake (Pirino et al 2022) which may be explained by the higher hepatic alcohol dehydrogenase activity in females compared to male rats (Quintanilla et al 2007). However, it is currently unclear whether the enhanced drinking in females is related to the reduced side effect potential in these animals and why we see no differences in alcohol preference in the 24-h drinking sessions.…”

Chronic Alcohol Drinking Drives Sex-Specific Differences in Affective Behavior and Medial Prefrontal Cortex Activity in CRF1:Cre:Tdtomato Transgenic Rats

“…Notably, there were no group effects of EtOH drinking on pain sensitivity or affective behavior. While previous studies have seen effects of EtOH on pain sensitivity and affect(Quadir et al, 2021b) (Gong et al, 2017; Overstreet et al, 2005; Van Skike et al, 2015; Xu et al, 2021), others studies have not (Bloch et al, 2020; McNamara and Ito, 2021; Pirino et al, 2022) One potential explanation is that rats in the present study only drank for 3-4 weeks before behavioral testing and thus did not consume enough EtOH to produce behavioral deficits. Studies in Wistar rats report escalated intake after ∼20 EtOH drinking sessions(Carnicella et al, 2009; George et al, 2012; Kimbrough et al, 2017); rats in this study only drank for 16 sessions.…”

Transgenerational Hangovers: A Rat Model for Behavioural and Epigenetic Changes Across Generations due to Paternal Preconceptual Alcohol Consumption

“…Females also consumed more ethanol than males in both the F1 and F2. This is not surprising as several previous studies has shown that drinking behaviour shows sex-based differences with females consuming greater amounts of ethanol per bodyweight (Hussain et al, 2022;Lancaster et al, 1996), showing higher preferences for ethanol than males (Hussain et al, 2022;Lancaster & Spiegel, 1992;Pirino et al, 2022;Priddy et al, 2017), developing drinking behaviour faster (Melón et al, 2013;Moore, C. F. & Lynch, 2015) and showing different drinking patterns across a session (Juárez & De Tomasi, 1999).…”

“…These baseline differences must be considered when looking at performance under ethanol because while we see similar performances under the influence of ethanol between the ND1 males and females, the females show a greater drop from baseline performance. Motor impairment due to ethanol has been reported to affect sexes differently (Hussain et al, 2022;Vetter-O'Hagen et al, 2009) This has been attributed to differences in alcohol metabolism with studies showing lower blood ethanol levels for the same ethanol dose (Mankes et al, 1991) and similar blood ethanol concentrations for greater ethanol intake (Pirino et al, 2022)in females compared to male rats.…”