Sex differences in ethanol reward seeking under conflict in mice

Qiaowei Xie

doi:10.17918/dfdb-4r19

Background: Inflexible alcohol seeking and drinking despite negative consequences - like depressed emotional state, health problems and economic burden - is a hallmark of alcohol use disorder in humans. This can be modeled in rodents using a task assessing alcohol seeking despite aversion. Males and females show different sensitivity to ethanol reward and to the development of inflexible alcohol seeking, but whether sex is a factor in reward-aversion conflict in ethanol seeking is unclear. It also has been shown that a history of ethanol dependence may result in excessive ethanol drinking behavior and might enhance compulsive ethanol seeking that persists under conflict. Here, we investigate whether male and female mice respond differently when ethanol seeking occurs under conflict, and whether a history of ethanol dependence alters this behavior in males and females. Methods: To investigate sex differences in ethanol reward seeking under conflict, adult male and female C57BL/6J mice were matched to undergo four cycles of chronic intermittent ethanol (CIE) exposure by vapor inhalation or serve as air-exposed controls. After ethanol exposure, mice were conditioned in a modified ethanol conditioned place preference paradigm that incorporated a single 0.8mA footshock in the ethanol-paired chamber. Time spent in and latency to enter the ethanol reward-paired chamber were assessed before and after the aversive experience. Results: The control and CIE-exposed males reduced time spent in the reward-paired chamber following an aversive experience. Control females did not reduce time spent in the ethanol-paired chamber following footshock. In contrast, CIE-exposed females exhibited increased time spent in the ethanol-paired chamber before footshock, but also showed greater reductions in time spent in the ethanol-paired chamber after shock. The change in time spent in and latency to enter reward-paired chamber were not observed in absence of footshock in both males and females. Neither sex nor CIE impacted sensitivity to in a one-paw retraction footshock threshold test. Conclusions: Our current study indicates that non-dependent female mice did not attenuate ethanol seeking following negative consequence and exhibited greater compulsive-like ethanol seeking behavior than males. Non-dependent males showed higher sensitivity to aversion-induced reduction of alcohol seeking than females, who exhibited compulsive-like ethanol reward seeking. CIE exposure did not affect ethanol seeking behavior in male mice in this model. Exposure to CIE increased the sensitivity to ethanol reward in dependent female as they showed increased ethanol seeking in the absence of conflict. However, CIE-exposed females reduced EtOH seeking in the presence of reward-aversion conflict, indicative of less compulsive-like ethanol seeking than nondependent females. We demonstrated that these behavioral differences were neither due to sex or CIE effects on extinction learning effect nor sensitivity to footshock. Together, our studies provide evidence that chronic ethanol exposure impacts compulsive-like ethanol seeking under conflict in a sex-specific manner and reveal the importance of the inclusion of females in studying neurobiological factors driving the development and expression of compulsive-like inflexible ethanol seeking.

Sex differences in ethanol reward seeking under conflict in mice

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Sex differences in ethanol reward seeking under conflict in mice

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