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以男性为导向的问题，因此对女性特有的风险因素的研究一直很少。然而，药物滥用方面的性别差距正在迅速缩小，来自动物和人类的研究结果表明，女性实际上比男性更容易吸毒。因此，迫切需要查明酒精和药物滥用风险因素的性别差异，以便制定针对性别的预防和治疗努力。一个明显的候选风险因素是糟糕的抑制性控制。最近的研究表明，卵巢激素雌二醇与抑制作用差有关，在大量年轻的成年饮酒者中，女性的抑制控制能力比男性差，无论是在抑制的基线水平上，还是在对酒精解除抑制效果的敏感度方面。本文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对大脑激活的影响程度；2)确定在反应抑制期间循环性激素和月经周期阶段对酒精对大脑激活影响的程度。对于这两个目标，在执行停止信号任务期间，将使用功能磁共振成像(FMRI)来评估反应抑制期间的大脑激活，该任务可靠地激活与抑制控制有关的右侧前额叶区域。妇女将在卵泡晚期和黄体中期进行测试。 将对月经周期和血清性激素(雌二醇、孕酮和睾酮)水平进行评估。对于目标2，在停止信号任务执行的fMRI期间，静脉注射酒精(60 mg%)和生理盐水。据推测，在反应抑制期间，雌二醇将与大脑激活呈负相关，因此女性的激活程度将低于男性，对酒精的影响更敏感，特别是在卵泡晚期，此时雌二醇水平较高。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)静脉注射酒精期间的功能磁共振成像；以及3)神经内分泌学。这些研究的结果将为R01的应用奠定基础，以纵向检查抑制性控制中基于生物学的性别差异是大量饮酒的原因或结果，或两者兼而有之的程度。拟议的培训计划将提供进行这一系列研究的下一步所需的独特技能，并为建立一个独立的研究计划铺平道路，该计划旨在确定酒精和药物滥用风险中性别差异的行为、神经和激素决定因素。

 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.