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

基本信息

批准号：
10604392
负责人：
ROBERT M ANTHENELLI
金额：
$ 70.4万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604392
关键词：
Acute Adrenal Glands Affect Affective Alcohols Amygdaloid structure Ataxia Blood alcohol level measurement Brain Brain region 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 Individual Interview Laboratories Laboratory Study 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 Procedures 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 breath alcohol measurement career drinking drug reward emerging adulthood emotion regulation experience experimental study falls feasibility trial hedonic hypothalamic-pituitary-adrenal axis imaging approach improved individual response innovation insight lens male men neurobiological mechanism neuroimaging pilot test response reward processing secondary analysis sedative segregation sex stress reactivity

项目摘要

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.

项目摘要我们实验室和其他人的证据发现，一个人对饮酒的敏感性成年预测未来与酒精有关的问题。尽管已经假设灵敏度与酒精耐受性，很少有研究对这种关系进行充分评估。此外，我们先前的研究已经鉴定出前额叶皮层（PFC）和边缘 - 高丘脑 - 垂体 - 肾上腺（LHPA）应力轴，它们与大脑的奖励电路相互作用，作为与A相关的潜在性敏感功能性脑网络人对酒精的反应水平低（LR）。到目前为止，基于功能磁共振成像（fMRI）与LR的关联已以隔离方式分析了大脑区域酒精作用，但没有考虑 PFC-LHPA网络与这些大脑电路中的性别差异之间的功能连通性（FC）。该提案的目标是进行一系列事后二级分析，两次可行性试验以及一项完整的人类实验室研究，结合了神经内分泌和乙醇-FMRI探测方法 PFC-LHPA网络通过聚焦于LR的镜头，酒精的刺激作用，急性的发展容忍和潜在的性别差异。我们假设低LR到酒精将与 PFC-LHPA网络之间的FC降低，而女性的FC中断将大于男性。为了检验这一假设，在R21阶段，我们将从现有数据集中重新分析fMRI数据，其中低LR和高LR的男女完成了酒精挑战，随后是乙醇/安慰剂-FMRI 情感处理任务。我们还将探索潜在的性别差异以及LR之间与酒精为：1）先前在实验室中测量的急性公差，以及2）随后的慢性发展公差在两个独特的现有数据集中纵向测量。最后，我们将进行两个飞行员的可行性研究R33的12个低LR和高LR男女的研究阶段：1）检查高剂量的主观和客观酒精敏感性和急性耐受性酒精； 2）检查酒精对脑激活和连通性模式的影响 - 以及刺激PFC-LHPA网络不同组成部分的压力处理fMRI任务。在R33阶段，我们将进行一组新的实验，以结合高剂量乙醇在R21阶段进行的神经内分泌挑战，然后是乙醇/安慰剂-FMRI程序。以前曾在60名年轻，中度饮酒，非酒精依赖的男女。该实验将允许美国测试低 - （n = 30）和高LR（n = 30）女性（50％），男性在压力激素上是否有所不同对暴饮暴食的反应，以及这些酒精敏感性和压力激素反应如何与PFC-LHPA网络中的功能连接相关。数据还将收集以评估通过内分泌和内分泌的变化来衡量的酒精的刺激性，享乐，共透性作用和急性耐受性 PFC-LHPA在低LR和高LR受试者之间的呼吸与呼吸量降低时进行了测量。