Sex Differences in Ethanol Reward Seeking Under Conflict in Mice

Alcohol use disorders are characterized by inflexible alcohol seeking that occurs despite adverse consequences. Males and females are differentially sensitive to ethanol (EtOH) reward, but it is unclear whether sex differences in EtOH seeking under reward-aversion conflict are present.

To investigate sex differences in EtOH seeking under conflict, adult male and female C57BL/6J mice underwent chronic intermittent EtOH (CIE) exposure by vapor inhalation or served as air-exposed controls. After CIE, mice were trained in a modified EtOH conditioned place preference paradigm. During 3 conditioning sessions, 2 g/kg EtOH was administered prior to confinement in the "EtOH-paired" chamber. On alternating days, saline was injected prior to confinement in the "saline-paired" chamber. After conditioning, mice experienced a footshock in the EtOH-paired chamber. EtOH-seeking behavior was assessed before and after footshock.

Control and CIE-exposed males reduced the time spent in and increased latency to enter the reward-paired chamber following footshock. Control females did not alter EtOH-seeking behavior following footshock. CIE-exposed females spent more time in the EtOH-paired chamber at baseline. However, following a footshock, CIE-exposed females significantly reduced the time spent in and increased latency to enter the EtOH-paired chamber.

Nondependent female mice exhibited aversion-resistant alcohol seeking to a greater degree than males. Chronic EtOH exposure did not impact EtOH seeking in males. In females, CIE enhanced EtOH seeking in the absence of conflict, but reduced EtOH seeking after an aversive experience. While these sex-specific effects of CIE are not present when reward seeking is assessed in the absence of an aversive experience, multiple factors may underlie the differences in reward seeking despite adverse consequences, including reward- and aversion-related learning and decision making under conflict. These data highlight the importance of considering sex as a variable influencing EtOH seeking and provide a greater understanding of how sex interacts with EtOH exposure to alter behavior.