Sex differences in basal motivated behavior, chronic ethanol drinking, and amygdala activity in female and male mice

Alcohol use disorder (AUD) is a major public health concern that despite its prevalence, lacks a widely-effective treatment due to the complexity of AUD pathology. AUD is highly comorbid with other psychiatric conditions including anxiety and mood disorders, however it is unclear how these disorders influence each other. The underlying etiology of these comorbidities is difficult to decipher and factors including sex, stress, and the environment further complicate both diagnosis and treatment strategies. To understand more about this bidirectional relationship between AUD and comorbid psychiatric disorders, we ran male and female C57Bl/6j mice through baseline behavioral testing followed by intermittent access-two bottle choice (IA-2BC) drinking. We found no sex differences in basal anxiety-like or depressive-like behavior, however females displayed enhanced motivated feeding behavior. Females consumed more ethanol than males, at both 1hr and 24hr timepoints. Basal affective state did not predict subsequent ethanol intake in either sex, however exploratory behavior was positively correlated with drinking in males but not females. We then re-assessed negative affect behavior following chronic ethanol drinking to determine if drinking impacted subsequent affective behavior and found no relationship between ethanol intake and affective state in males or females. We also examined how chronic ethanol drinking affected central amygdala (CeA) and basolateral amygdala (BLA) neuronal activity in males and females. Ethanol-drinking females had a decrease in CeA neuronal activity, driven by reduced activity in the lateral (CeA_l) sub-region, while in males there was no significant difference in CeA activity compared to water controls. Neither males or females had a significant change in BLA neuronal activity following chronic ethanol drinking. Collectively, these results demonstrate sex differences in basal motivated behavior, drinking behavior, and subregion-specific amygdala neuronal activity following chronic ethanol drinking which may inform the sex differences seen in patients diagnosed with AUD and comorbid conditions.