Neurobiological factors underlying sex differences in risk for alcohol abuse

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 DESCRIPTION (provided by applicant): Substance abuse has been traditionally considered a male-oriented problem and as a consequence research on risk factors specific to women has been minimal. However, the gender gap in substance abuse is closing rapidly, and findings from both animal and human studies suggest that females are actually more vulnerable to drug use than males. As such, there is an urgent need to identify sex differences in risk factors for alcoho and drug abuse in order to develop sex-specific prevention and treatment efforts. One clear candidate risk factor is poor inhibitory control. Recent studies suggest that the ovarian hormone estradiol is associated with poor inhibition, and that among heavy young adult drinkers, women have poorer inhibitory control than men, both in terms of baseline levels of inhibition and sensitivity to the disinhibiting effects of alcohol. The studies proposed here will determine the neural and hormonal mechanisms underlying this sex difference by addressing two specific aims: 1) to determine the degree to which circulating sex hormones, menstrual cycle phase, and sex influence brain activation during response inhibition, and 2) to determine the degree to which circulating sex hormones and menstrual cycle phase influence alcohol effects on brain activation during response inhibition in women. For both aims, brain activation during response inhibition will be assessed using functional magnetic resonance imaging (fMRI) during performance of the stop signal task, which reliably activates right-lateralized prefrontal regions implicated in inhibitory control. Women will be tested in the late follicular and mid-luteal phases of the menstrual cycle, and serum levels of sex hormones (estradiol, progesterone, and testosterone) will be assessed. For Aim 2, alcohol (60mg%) and saline will be administered intravenously during fMRI of stop signal task performance. It is hypothesized that estradiol will be inversely related to brain activation during response inhibition, such that women will have less activation than men and be more sensitive to the effects of alcohol, particularly in the late follicular phase, when estradiol is high. Completion of this research plan, in conjunction with the career development plan including mentor-directed training, formal coursework, and workshops, will provide training in three critical domains: 1) fMRI; 2) fMRI during IV alcohol infusion; and 3 neuroendocrinology. Results from these studies will lay the foundation for an R01 application to longitudinally examine the degree to which biologically-based sex differences in inhibitory control are a cause or consequence, or both, of heavy drinking. The proposed training plan will provide the unique skill set necessary to conduct the next steps in this line of research and pave the way for establishing an independent program of research aimed at determining the behavioral, neural, and hormonal determinants of sex differences in risk for alcohol and drug abuse.