Single prolonged stress in mice: interactions between alcohol drinking, negative affect, and fear learning

Abstract

Rationale & objective: Exposure to traumatic stressors can have detrimental effects on one’s well-being. Alcohol is often used as a coping mechanism to alleviate stress, leading to the development of alcohol use disorder (AUD). Furthermore, sex dimorphisms in stress and AUD alter their progression and sustenance. To investigate these interactions for effective treatment strategies, validated and exhaustive preclinical models are necessary. Here, we designed a comprehensive study that examines how traumatic stress influences ethanol drinking patterns and PTSD-like phenotypes in male and female mice with Single Prolonged Stress (SPS). Methods: Male and female C57BL/6 J mice underwent SPS, a model of traumatic stress consisting of a series of consecutive stressors, followed by a 7-day stress incubation period. Mice then underwent a series of tests for aversive state, fear discrimination, and drinking patterns during continuous and limited ethanol access. Results & conclusions: SPS selectively increased negative affect and startle responses in male mice, while females were unaffected. SPS disrupted discrimination adjustment between fear and safety cues during extinction, while ethanol exposure attenuated overall fear responses. SPS maintained baseline sex differences in consumption. Furthermore, female consumption increased when access was provided prior to and continuously throughout SPS and fear conditioning, contrasting with groups exposed to ethanol afterwards. In summary, we identified a distinct sex specific relationship between traumatic stress, fear memory, and the timing of ethanol consumption. We highlight SPS as a robust translational model for exploring the sex-specific neurobiological mechanisms driving traumatic stress-induced affective disturbances.