Sex differences in low‐dose ethanol effects on motivated behavior and limbic corticostriatal activity in mice

BACKGROUND: Even at lower doses, ethanol exposure impacts both the brain and behavior. Emerging work has shown that chronic exposure to lower doses of ethanol may lead to inflexible behaviors and promote aberrant reward seeking. This study investigated the impact of chronic, low-dose ethanol exposure on neural substrates of reward and on motivated behavior. METHODS: Adult C57BL/6J mice were trained to self-administer sucrose. Throughout training, mice received an injection of low-dose ethanol (0.5 g/kg) or saline, 1 h after each session. Mice did not receive ethanol during testing. Mice were then tested in a progressive ratio task where the reward magnitude of reinforcer was reduced (small or large) or increased (small or large). A subset of mice expressed a retrograde tracer in the nucleus accumbens (NAc), and cFos expression within NAc circuits was analyzed following a sucrose self-administration session. RESULTS: Chronic low-dose ethanol exposure altered behavioral responding in female mice following small changes in reward magnitude. Female mice showed divergent response patterns when there was a small reduction in reward magnitude, with greater proportions of ethanol-exposed female mice either increasing or decreasing responding versus controls. Following a small increase, low-dose ethanol female mice significantly increased responding versus controls. Female-but not male-mice exposed to chronic low-dose ethanol shifted behavioral strategy with a reduction in magazine "checking" behavior. Low-dose ethanol exposure altered cFos expression within the prelimbic cortex and its projections to the NAc during reward seeking. CONCLUSIONS: Chronic, low-dose ethanol altered behavioral responding and strategy in female mice in response to changes in reward value. Low-dose ethanol exposure impacted cFos induction in prelimbic cortex and its projections to NAc in both female and male mice. Future studies should investigate the consequences of chronic, low-dose ethanol on brain and behavior to understand what underlying processes drive aberrant reward-seeking behaviors.