Neurobiological factors underlying sex differences in risk for alcohol abuse

酒精滥用风险性别差异背后的神经生物学因素

• 批准号: 9221935
• 负责人: Jessica J Weafer
• 金额: $ 12.22万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9221935
• 关键词: Address; Affect; Alcohol abuse; Alcohols; Animals; Behavioral; Biological; Brain; Data; Development; Development Plans; Drug abuse; Educational workshop; Emotional; Estradiol; Female; Foundations; Functional Magnetic Resonance Imaging; Gender; Goals; Gonadal Steroid Hormones; Heavy Drinking; Hormonal; Human; Impairment; Individual; Infusion procedures; Intravenous; Laboratories; Link; Luteal Phase; Menstrual cycle; Mentors; Neurobiology; Neuroendocrinology; Ovarian hormone; Performance; Pharmaceutical Preparations; Phase; Prevention; Prevention strategy; Progesterone; Research; Risk; Risk Factors; Saline; Serum; Sex Characteristics; Signal Transduction; Societies; Source; Substance abuse problem; Task Performances; Testing; Testosterone; Training; Wit; Woman; alcohol effect; alcohol response; alcohol risk; base; behavior measurement; career development; drug use vulnerability; male; men; neurobiological mechanism; programs; proliferative phase Menstrual cycle; public health relevance; relating to nervous system; response; sex; skills; sobriety; treatment strategy; young adult

 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.

 描述（由申请人提供）：药物滥用传统上被认为是男性问题，因此对女性特有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，迫切需要确定酒精和药物滥用危险因素的性别差异，以便制定针对性别的预防和治疗工作。一个明显的候选危险因素是抑制控制不佳。最近的研究表明，卵巢激素雌二醇与抑制能力差有关，在大量年轻饮酒者中，女性的抑制控制能力比男性差，无论是在抑制基线水平还是对酒精去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，2）确定循环性激素和月经周期阶段影响女性反应抑制期间酒精对大脑激活的影响的程度。对于这两个目标，将在执行停止信号任务期间使用功能磁共振成像（fMRI）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。女性将在卵泡晚期和黄体中期接受测试 月经周期的变化，以及性激素（雌二醇、黄体酮和睾酮）的血清水平将被评估。对于目标 2，将在执行停止信号任务的 fMRI 期间静脉注射酒精 (60mg%) 和盐水。据推测，雌二醇在反应抑制期间与大脑激活呈负相关，因此女性的激活程度低于男性，并且对酒精的影响更敏感，特别是在卵泡晚期，此时雌二醇较高。结合本研究计划完成 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）静脉输注酒精期间的fMRI；和3神经内分泌学。这些研究的结果将为 R01 应用奠定基础，以纵向研究抑制控制中基于生物学的性别差异是酗酒的原因或结果或两者的程度。拟议的培训计划将提供开展这一研究领域后续步骤所需的独特技能，并为建立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性别差异的行为、神经和激素决定因素。