Sex differences in nucleus accumbens circuitry engaged with binge-like ethanol drinking.

Rationale: Women tend to progress from initial alcohol use to Alcohol Use Disorder (AUD) more quickly than men, highlighting the need to study sex differences in models of early-stage alcohol use. In humans and rodents, the nucleus accumbens (NAc) regulates alcohol binge drinking, a risk factor for developing AUD. However, it is unknown whether similar brain regions and NAc inputs are engaged in males and females during binge-like drinking.

Methods: We labeled NAc inputs with a viral retrograde tracer (GFP) and quantified whole-brain c-Fos to determine the regions and NAc inputs differentially engaged in male and female mice during binge-like drinking. Mice underwent a 4-day Drinking-in-the-Dark task for either ethanol or water. Immediately following drinking on day 4, periorbital blood samples were collected for determination of blood ethanol concentration, and brains were collected. c-Fos expression and c-Fos + GFP colocalization was quantified for 426 brain areas using SmartAnalytics. We employed several data and network analysis approaches to identify NAc circuits and regions engaged, and network dynamics altered by binge-like drinking.

Results: We found that ethanol engaged significantly more NAc inputs in binge-like ethanol drinking females, as compared to males, including various GABAergic and glutamatergic regions. Moreover, we found that binge-like drinking females had 129 brain areas with greater c-Fos than males. Relative to water controls, ethanol increased network modularity and decreased connectivity in both sexes and did so more dramatically in males.

Conclusion: Our results support that early-stage binge-like ethanol drinking engages brain regions and NAc inputs and alters network dynamics in a sex-specific manner, which may help to explain the faster transition from initial alcohol use to AUD in women.