Exploring Potential Sex Differences In Neurobiological Mechanisms of Alcohol Sensitivity and Tolerance

探索酒精敏感性和耐受性的神经生物学机制中潜在的性别差异

• 批准号: 9895371
• 负责人: ROBERT M ANTHENELLI
• 金额: $ 20.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895371
• 关键词: Acute; Adrenal Glands; Affect; Affective; Alcohols; Amygdaloid structure; Ataxia; Blood alcohol level measurement; Brain; Chronic; Corticotropin; Data; Data Set; Development; Diagnostic; Dose; Emotional; Emotional Stress; Endocrine; Ethanol; Exhibits; Face; Feasibility Studies; Female; Functional Magnetic Resonance Imaging; Future; Goals; Hormonal; Hormones; Human; Hydrocortisone; Hypothalamic structure; Imaging Techniques; Individual; Interview; Laboratories; Laboratory Study; Lead; Life; Limb structure; Link; Measures; Modeling; Neurosecretory Systems; Pathway interactions; Patient Self-Report; Pattern; Persons; Pharmaceutical Preparations; Phase; Pituitary Gland; Pituitary-Adrenal System; Placebos; Plasma; Prefrontal Cortex; Property; Research; Rest; Rewards; Seminal; Series; Sex Differences; Stress; Structure; Testing; Trier Social Stress Test; Woman; Work; alcohol effect; alcohol related problem; alcohol response; alcohol sensitivity; alcohol use disorder; base; breath alcohol measurement; career; drinking; drug reward; emerging adulthood; emotion regulation; experience; experimental study; falls; feasibility trial; hedonic; human imaging; hypothalamic-pituitary-adrenal axis; imaging approach; improved; individual response; innovation; insight; lens; male; men; neurobiological mechanism; neuroimaging; response; reward processing; secondary analysis; sedative; sex; stress reactivity

Project Summary Evidence from our lab and others finds that an individual's sensitivity to alcohol in emerging adulthood predicts future alcohol-related problems. Although sensitivity has been hypothesized to relate to alcohol tolerance, few studies have adequately evaluated that relationship. In addition, our prior research has identified the prefrontal cortex (PFC) and limbic-hypothalamic-pituitary-adrenal (LHPA) stress axis, which interact with the brain's reward circuit, as a potential sex-sensitive functional brain network associated with a person's low level of response (LR) to alcohol. Until now, functional magnetic resonance imaging (fMRI)-based associations with LR have analyzed brain regional alcohol effects in a segregated manner and did not consider the functional connectivity (FC) between the PFC-LHPA network and sex differences in these brain circuits. The goals of this proposal are to conduct a series of post-hoc secondary analyses, two pilot feasibility trials, and a full human laboratory study that combines neuroendocrine and ethanol-fMRI approaches to probe the PFC-LHPA network through a lens focused on LR, alcohol's stimulating effects, the development of acute tolerance, and potential sex differences. We hypothesize that low LR to alcohol will be correlated with decreased FC between the PFC-LHPA network and that disrupted FC will be greater in women than men. To test this hypothesis, in the R21 phase we will reanalyze fMRI data from an existing data set wherein low- and high-LR women and men completed an alcohol challenge followed by an ethanol/placebo-fMRI emotional processing task. We will also explore potential sex differences and the relations among LR to alcohol with: 1) acute tolerance measured previously in the lab, and 2) the subsequent development of chronic tolerance measured longitudinally in two unique existing data sets. Finally, we will conduct two pilot feasibility studies in 12 low- and high-LR women and men that will serve as Go / No-Go decision points for the R33 phase: 1) examine subjective and objective alcohol sensitivity measures and acute tolerance to a higher dose of alcohol; and 2) examine alcohol's effects on brain activation and connectivity patterns following emotional- and stress-processing fMRI tasks that stimulate different components of the PFC-LHPA network. In the R33 phase, we will conduct a new set of experiments combining a higher-dose ethanol neuroendocrine challenge piloted in the R21 phase followed by the ethanol/placebo-fMRI procedure piloted previously in 60 young, moderate drinking, non-alcohol dependent women and men. That experiment will allow us to test whether low- (N = 30) and high-LR (N = 30) women (50%) and men differ in their stress hormone response to a binge-like drinking episode, and how those alcohol sensitivity and stress hormone responses correlate with functional connectivity in the PFC-LHPA network. Data will also be gathered to evaluate alcohol's stimulating, hedonic, ataxic effects and acute tolerance as measured by changes in endocrine and PFC-LHPA measures at rising versus falling breath alcohol concentrations between low- and high-LR subjects.

项目概要 我们实验室和其他实验室的证据发现，一个人对酒精的敏感度会随着年龄的增长而增加。 成年期预示着未来与酒精相关的问题。尽管敏感性被假设与 酒精耐受性，但很少有研究充分评估这种关系。此外，我们之前的研究已经 确定了前额皮质（PFC）和边缘-下丘脑-垂体-肾上腺（LHPA）应力轴， 与大脑的奖励回路相互作用，作为与性别相关的潜在的性别敏感功能性大脑网络 人对酒精的低反应水平（LR）。到目前为止，基于功能磁共振成像（fMRI）的 与 LR 的关联以分离的方式分析了大脑区域酒精的影响，并且没有考虑 PFC-LHPA 网络之间的功能连接 (FC) 以及这些大脑回路中的性别差异。 该提案的目标是进行一系列事后二次分析，两个试点可行性 试验以及一项完整的人体实验室研究，结合了神经内分泌和乙醇功能磁共振成像方法来探测 PFC-LHPA 网络通过聚焦于 LR、酒精的刺激作用、急性发作的发展的镜头 耐受性和潜在的性别差异。我们假设对酒精的低 LR 与 PFC-LHPA 网络之间的 FC 减少和 FC 中断在女性中比男性更大。 为了检验这一假设，在 R21 阶段，我们将重新分析现有数据集中的 fMRI 数据，其中 低和高 LR 女性和男性完成酒精挑战，然后进行乙醇/安慰剂功能磁共振成像 情绪处理任务。我们还将探讨潜在的性别差异以及 LR 之间的关系 酒精具有以下特征：1) 先前在实验室测量的急性耐受性，以及 2) 随后发展为慢性耐受性 在两个独特的现有数据集中纵向测量的公差。最后，我们将进行两次试点可行性 对 12 名低 LR 和高 LR 女性和男性进行的研究将作为 R33 的 Go/No-Go 决策点 阶段：1）检查主观和客观酒精敏感性测量以及对较高剂量的急性耐受性 酒精； 2）检查酒精对情绪后大脑激活和连接模式的影响 以及刺激 PFC-LHPA 网络不同组成部分的压力处理功能磁共振成像任务。 在R33阶段，我们将进行一组新的实验，结合更高剂量的乙醇 在 R21 阶段试行神经内分泌挑战，然后试行乙醇/安慰剂-fMRI 程序 此前曾在 60 名年轻、适度饮酒、无酒精依赖的女性和男性中进行过研究。该实验将允许 我们测试低 LR (N = 30) 和高 LR (N = 30) 女性 (50%) 和男性的压力激素是否存在差异 对暴饮暴食的反应，以及酒精敏感性和应激激素的反应 与 PFC-LHPA 网络中的功能连接相关。还将收集数据进行评估 酒精的刺激、享乐、共济失调作用和急性耐受性（通过内分泌和代谢的变化来衡量） PFC-LHPA 测量低 LR 和高 LR 受试者之间呼吸酒精浓度的上升与下降。