Shortening Time for Alcohol Access Drives Up Front-Loading Behavior, Bringing Consumption in Male Rats to the Level of Females

Abstract

Alcohol can have more detrimental effects on mental health in women, even when intake is comparable or higher in men. This may relate to a differential pattern of drinking, e.g., how rapidly alcohol is consumed. We used operant procedures to gain insight into sex differences in the drinking dynamics of rats. Adult male and female Wistar rats underwent operant training to promote voluntary drinking of 10% (w/v) alcohol (8 rats/sex). We tested how drinking patterns changed after manipulating the effort required for alcohol (fixed ratio, FR), as well as the length of time in which animals had access to alcohol (self-administration session length). Rats were tested twice within the 12 hours of the dark cycle, at 2 hours (early sessions) and 10 hours into the dark cycle (late sessions). As expected, adult females consumed significantly more alcohol than males in the 30-minute sessions with the FR1 paradigm. Alcohol consumption within females was higher in the late sessions compared to early sessions, whereas this difference was not found within males. Front-loading of alcohol (heavier drinking in the first five minutes of the session) was the primary factor underlying higher consumption in females, and this sex difference was accentuated in the late sessions. Increasing the effort required from FR1 to FR3 reduced alcohol drinking in both sexes. Front-loading behavior remained in females in both early and late sessions, whereas males exhibited minimal front-loading behavior only in the early sessions. Compressing drinking access to 15-minutes drove up front-loading behavior, producing total alcohol intake levels that were comparable in both sexes. This strategy could be useful for exploring sex differences in the effect of voluntary alcohol drinking on the brain. Our findings also highlight the importance of the time of testing for detecting sex differences in drinking behavior.

A Critical Review of Front-loading: A Maladaptive Drinking Pattern Driven by Alcohol's Rewarding Effects

“…Therefore, front-loading may contribute to the higher alcohol intake seen in alcohol vaporexposed animals, and it is possible that negative reinforcement could be a driving factor in the maintenance of front-loading behavior. However, this does not rule out the possibility that frontloading is driven by alcohol's rewarding effects and it should also be noted that alcohol frontloading has been reported in rodents who do not self-administer alcohol at levels which would induce dependence (Flores-Bonilla et al, 2021, Linsenbardt and Boehm, 2014, Bauer et al, 2021, Jeanblanc et al, 2019. Another way of summarizing this is that although negative reinforcement as a driver of front-loading cannot be ruled out, limited current data suggest that it is neither necessary nor sufficient for front-loading to develop.…”

“…Female rodents typically outdrink males during alcohol self-administration. This phenomenon has been reported across different species and selfadministration protocols (Sneddon et al, 2020, Li et al, 2019, Oberlin et al, 2011, Priddy et al, 2017, Lourdes de la Torre et al, 2015; and there is new evidence directly linking front-loading in female rats as the reason for their higher total alcohol intake during operant selfadministration (Flores-Bonilla et al, 2021). Further, it has been reported that female B6 mice with a binge drinking history front-load more quinine-adulterated alcohol than males (Bauer et al, 2021).…”

A critical review of front‐loading: A maladaptive drinking pattern driven by alcohol's rewarding effects

“…Female rodents typically outdrink males during alcohol self‐administration. This phenomenon has been reported across different species and self‐administration protocols (Li et al, 2019; Lourdes de la Torre et al, 2015; Oberlin et al, 2011; Priddy et al, 2017; Sneddon et al, 2020); and there is new evidence directly linking front‐loading in female rats as the reason for their higher total alcohol intake during operant self‐administration (Flores‐Bonilla et al, 2021). Further, it has been reported that female B6 mice with a binge drinking history front‐load more quinine‐adulterated alcohol than males (Bauer et al, 2021).…”

“…Therefore, front‐loading may contribute to the higher alcohol intake seen in alcohol vapor‐exposed animals, and it is possible that negative reinforcement could be a driving factor in the maintenance of front‐loading behavior. However, this does not rule out the possibility that front‐loading is driven by alcohol's rewarding effects and it should also be noted that alcohol front‐loading has been reported in rodents who do not self‐administer alcohol at levels which would induce dependence (Bauer et al, 2021; Flores‐Bonilla et al, 2021; Jeanblanc et al, 2019; Linsenbardt & Boehm, 2014). Another way of summarizing this is that although negative reinforcement as a driver of front‐loading cannot be ruled out, limited current data suggest that it is neither necessary nor sufficient for front‐loading to develop.…”

Greater resistance to footshock punishment in female C57BL/6J mice responding for ethanol

“…It is also important to consider that the observed results may be specific to the experimental parameters employed here. For example, female rats have been shown to respond more than males for 10% EtOH when an FR1 schedule of reinforcement is used (Flores-Bonilla et al, 2021). Interestingly, in agreement with our own work, this sex difference was not observed with an FR3 schedule of reinforcement.…”