Presence of distinct operant phenotypes and transient withdrawal-induced escalation of operant ethanol intake in female rats

Operant self-administration is frequently used to investigate the neurobiological mechanisms underlying alcohol seeking and drinking and to test the efficacy of drugs under development for the treatment of alcohol use disorder (AUD). Although widely used by the research community, there is a paucity of operant ethanol self-administration studies that include female subjects. The current study characterizes home cage drinking and operant ethanol self-administration in female Sprague Dawley, Long Evans, and Wistar rats. Rats underwent three weeks of intermittent-access two-bottle choice home cage drinking before being trained to lever press for ethanol in standard operant chambers equipped with contact lickometers. After capturing baseline operant performance, rats were chronically exposed to control or ethanol liquid diet using the Lieber-DeCarli method. Operant ethanol self-administration was re-evaluated after chronic liquid diet exposure to determine whether female rats exhibit similar withdrawal-induced escalation of ethanol intake as is regularly observed in male rats. Our findings reveal the presence of three distinct operant phenotypes (Drinker, Responder, Nonresponder), the prevalence of which within each strain is strikingly similar to our previous observations in males. Within a given phenotype, rats of each strain performed similarly during operant testing. Ethanol intake during home cage drinking was unable to predict future operant phenotype. Relative to controls, Drinkers chronically exposed to ethanol liquid diet exhibited a significant, but transient, escalation in consummatory, but not appetitive, responding during acute withdrawal. Collectively, these data closely parallel many of our previous observations in males while also highlighting potential sex differences in drinking strategies following dependence. The presence of the Responder phenotype reinforces the importance of using direct measures of ethanol consumption. Our findings provide new insight into similarities and differences in operant ethanol self-administration between males and females and emphasize the importance of including females in future studies of ethanol drinking and dependence.