Sex Differences in Risk for Alcohol Use Disorder: Neural and Hormonal Influences

PROJECT SUMMARY/ABSTRACT The sex gap in alcohol consumption is closing rapidly, due to alarming increases in alcohol consumption among young women. As such, there is an urgent need to determine the factors underlying sex differences in risk for AUD. Current addiction models propose three neurofunctional domains that drive problematic alcohol use and therefore serve as candidate sex-specific risk factors: executive function, negative emotionality, and incentive salience. Data from our lab and others suggest that poor inhibitory control, a key component of executive function, is a stronger risk factor for women than for men. Moreover, we have preliminary evidence that female drinkers show less engagement of neural circuitry underlying inhibitory control, and that this sex difference is influenced by circulating levels of estradiol. However, the degree to which hormonally-moderated sex differences in executive function extend to the negative emotionality and incentive salience domains, and how these sex differences influence current and future drinking is unknown. Here we will determine: 1) the neurobiological factors contributing to sex-specific risk for AUD in each of these three addiction domains and 2) the degree to which sex differences in each domain influence current and prospective drinking. Female drinkers will undergo fMRI to assess neural correlates of inhibitory control (i.e., executive function), negative emotionality, and alcohol cue reactivity (i.e., incentive salience) at three phases of their menstrual cycle: early follicular phase (low estradiol, low progesterone), late follicular phase (high estradiol, low progesterone), and mid-luteal phase (moderate estradiol, high progesterone). Male drinkers will undergo three fMRI scans at matched intervals. Immediately following each scan, participants will complete a session of free-access intravenous alcohol self-administration. We will then follow participants for 18 months to longitudinally assess changes in drinking patterns. We hypothesize that hormonally-moderated neural function underlying inhibitory control and negative emotionality will be stronger predictors of current and future alcohol consumption in women compared to men, whereas neural alcohol cue reactivity will be a stronger predictor for men. The project capitalizes on the unique skill sets of the PI (an Early Career Investigator) and a strong, collaborative investigative team. The innovative design will provide essential information regarding neural factors influencing development and maintenance of AUD, and, critically, how this risk is influenced by sex and fluctuations in sex hormones. Ultimately, this proposal is a crucial step in a line of research that will lead to the development of sex-specific prevention and treatment efforts for AUD.