Neurobiological factors underlying sex differences in risk for alcohol abuse

 描述（由申请人提供）：药物滥用传统上被认为是一个面向男性的问题，因此对女性特有的风险因素的研究很少。然而，药物滥用方面的性别差距正在迅速缩小，动物和人类研究的结果表明，女性实际上比男性更容易吸毒。因此，迫切需要查明酗酒和吸毒风险因素的性别差异，以便开展针对性别的预防和治疗工作。一个明显的候选风险因素是抑制控制不良。最近的研究表明，卵巢激素雌二醇与抑制作用差有关，在重度年轻饮酒者中，女性的抑制控制能力比男性差，无论是在抑制的基线水平还是对酒精解除抑制作用的敏感性方面。这里提出的研究将通过解决两个具体目标来确定这种性别差异背后的神经和激素机制：1）确定循环性激素、月经周期阶段和性别在反应抑制期间影响大脑激活的程度，和2）为了确定循环性激素和月经周期阶段在多大程度上影响酒精对反应抑制期间大脑激活的影响，妇女对于这两个目标，将使用功能性磁共振成像（fMRI）在执行停止信号任务期间评估反应抑制期间的大脑激活，该任务可靠地激活了与抑制控制有关的右侧前额叶区域。女性将在卵泡晚期和黄体中期进行检测 并评估性激素（雌二醇、孕酮和睾酮）的血清水平。对于目标2，将在停止信号任务执行的fMRI期间静脉内给予酒精（60 mg %）和生理盐水。据推测，在反应抑制过程中，雌二醇与大脑激活呈负相关，因此女性的激活程度低于男性，对酒精的影响更敏感，特别是在雌二醇高的卵泡晚期。完成这项研究计划，与 职业发展计划，包括导师指导的培训，正式的课程，和研讨会，将提供三个关键领域的培训：1）功能磁共振成像; 2）功能磁共振成像在静脉酒精输液;和3神经内分泌学。这些研究的结果将奠定基础的R 01应用程序纵向检查在何种程度上基于生物学的性别差异抑制控制的原因或后果，或两者兼而有之，大量饮酒。拟议的培训计划将提供必要的独特技能，以进行下一步的研究，并铺平道路，建立一个独立的研究计划，旨在确定行为，神经和激素的决定因素的性别差异的风险酒精和药物滥用。

 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.