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

项目摘要 来自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性， 成年期预示着未来酒精相关的问题。尽管敏感性被假设为与 酒精耐受性，很少有研究充分评估这种关系。此外，我们之前的研究 确定了前额叶皮层（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，作为一个潜在的性敏感功能性大脑网络， 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） 与LR的关联已经以隔离的方式分析了大脑区域酒精的影响， PFC-LHPA网络之间的功能连接（FC）和这些脑回路的性别差异。 本提案的目标是进行一系列事后二次分析， 一项完整的人类实验室研究，结合神经内分泌和乙醇功能磁共振成像方法， PFC-LHPA网络通过一个透镜关注LR，酒精的刺激作用，急性 耐受性和潜在的性别差异。我们假设，低LR酒精将与 PFC-LHPA网络之间的FC减少和FC中断在女性中比男性更大。 为了验证这一假设，在R21阶段，我们将重新分析来自现有数据集的fMRI数据，其中 低和高LR的女性和男性完成酒精挑战，然后进行乙醇/安慰剂fMRI 情绪处理任务我们还将探讨潜在的性别差异和LR之间的关系， 酒精与：1）先前在实验室中测量的急性耐受性，以及2）随后的慢性发展 在两个独特的现有数据集中纵向测量的公差。最后，我们将进行两个试点的可行性研究 在12名低和高LR女性和男性中进行的研究，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指标以及对较高剂量的急性耐受性 2）研究酒精对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fMRI任务。 在R33阶段，我们将进行一组新的实验， 在R21阶段进行神经内分泌激发试验，随后进行乙醇/安慰剂-fMRI程序试验 以前在60名年轻，适度饮酒，非酒精依赖的女性和男性。这个实验将允许 我们测试低-（N = 30）和高-LR（N = 30）女性（50%）和男性在应激激素方面是否存在差异 对酗酒的反应，以及这些酒精敏感性和应激激素反应 与PFC-LHPA网络中的功能连接相关。还将收集数据以评估 酒精的刺激，享乐，共济失调的影响和急性耐受性，通过内分泌和 PFC-LHPA测量低和高LR受试者之间呼气酒精浓度的上升与下降。

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.