Sensitivity to Intravenous Ethanol: Neuroimaging and Behavioral Phenotypes

对静脉注射乙醇的敏感性：神经影像和行为表型

• 批准号: 8269633
• 负责人: Eric D Claus
• 金额: $ 19.64万
• 依托单位: THE MIND RESEARCH NETWORK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8269633
• 关键词: Acclimatization; Accounting; Acute; Advocate; Alcohol consumption; Alcohol dependence; Alcohols; Animals; Anterior; Area; Base of the Brain; Behavior; Behavioral; Biological Markers; Blood; Blood alcohol level measurement; Brain; Characteristics; Data; Detection; Disinhibition; Dopamine; Environment; Ethanol; Event-Related Potentials; Feasibility Studies; Functional Magnetic Resonance Imaging; Future; Genetic; Genetic Variation; Goals; Heart Rate; Heavy Drinking; Human; Impulsivity; Incentives; Individual; Inferior frontal gyrus; Infusion procedures; Intoxication; Intravenous; Lateral; Limb structure; Literature; Measurement; Measures; Motivation; Motor; Neurobiology; Neurocognitive; Nucleus Accumbens; Oral; Outcome; Patient Self-Report; Phenotype; Physiological; Recording of previous events; Recruitment Activity; Research; Risk; Sedation procedure; Staging; Time; Translations; Ventral Striatum; alcohol cue; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; base; binge drinking; blood oxygenation level dependent response; cognitive control; drinking; drinking behavior; endophenotype; high risk; indexing; neuroimaging; neuromechanism; novel; pharmacokinetic model; programs; relating to nervous system; response; young adult

DESCRIPTION (provided by applicant): Individual variability in alcohol sensitivity is among the most widely studied endophenotypes for alcohol dependence. However, little is known about brain mechanisms relevant for alcohol sensitivity. Research on human alcohol sensitivity phenotypes has often relied on self-report measures and conventional oral alcohol administration paradigms, both of which may introduce considerable measurement error, thus decreasing sensitivity for detecting genetic and neural correlates. The proposed study will examine neural markers of alcohol sensitivity in the context of an alcohol challenge paradigm that incorporates highly controlled intravenous ethanol infusion. The broad aims of this proposal include a) developing our approach for integrating fMRI and infusion; b) examining feasibility of studying neural correlates of alcohol sensitivity in this context; and c) estimating effect sizes to inform power analyses for future studies. Heavy-drinking young adults will participate in two infusion sessions: a baseline "acclimation" session and an fMRI session. Physiologically- Based Pharmacokinetic (PBPK) modeling will be used to establish a peak target blood alcohol concentration (BAC) of 0.06 1 0.005 g% within 15 minutes. This BAC will be maintained (clamped) for 90 minutes. Alcohol sensitivity indices will include traditional self-report measures; heart rate response during infusion; and serial measures of subjective intoxication (stimulation/sedation) across the session. We will examine these indicators in relation to BOLD responses during tasks that engage incentive motivation and cognitive control networks, incorporating repeated assessments across the BAC time course. Both traditional and brain-based measures of alcohol sensitivity will be examined in relation to self-reported drinking. By examining neural phenotypes in the context of acute alcohol exposure, we hope to identify brain-based alcohol sensitivity phenotypes that are potentially more sensitive to genetic variation and to behavioral outcomes as compared to traditional measures. )

描述（由申请人提供）：酒精敏感性的个体差异是酒精依赖性研究最广泛的内表型之一。然而，人们对与酒精敏感性相关的大脑机制知之甚少。对人类酒精敏感性表型的研究通常依赖于自我报告测量和传统的口服酒精给药范式，这两者都可能引入相当大的测量误差，从而降低检测遗传和神经相关因素的敏感性。拟议的研究将在酒精挑战范式的背景下检查酒精敏感性的神经标志物，其中包括高度控制的静脉内乙醇输注。该提案的主要目标包括：a) 开发我们的功能磁共振成像和输注整合方法； b) 检验在这种情况下研究酒精敏感性神经相关性的可行性； c) 估计效应大小，为未来研究的功效分析提供信息。酗酒的年轻人将参加两次输液课程：基线“适应”课程和功能磁共振成像课程。基于生理学的药代动力学 (PBPK) 模型将用于在 15 分钟内建立 0.06 1 0.005 g% 的峰值目标血液酒精浓度 (BAC)。该 BAC 将保持（夹紧）90 分钟。酒精敏感性指数将包括传统的自我报告措施；输注期间的心率反应；以及整个疗程中主观中毒（刺激/镇静）的一系列测量。我们将在涉及激励动机和认知控制网络的任务中检查这些与大胆反应相关的指标，并在 BAC 时间过程中纳入重复评估。传统的和基于大脑的酒精敏感性测量方法都将根据自我报告的饮酒情况进行检查。通过检查急性酒精暴露背景下的神经表型，我们希望识别基于大脑的酒精敏感性表型，与传统措施相比，这些表型可能对遗传变异和行为结果更敏感。 ）

项目成果

Genomic and structural characterization of Kunitz-type peptide LmKTT-1a highlights diversity and evolution of scorpion potassium channel toxins.

Kunitz 型肽 LmKTT-1a 的基因组和结构表征突出了蝎子钾通道毒素的多样性和进化。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Chen, Zongyun;Luo, Fan;Feng, Jing;Yang, Weishan;Zeng, Danyun;Zhao, Ruiming;Cao, Zhijian;Liu, Maili;Li, Wenxin;Jiang, Ling;Wu, Yingliang
• 通讯作者: Wu, Yingliang

Fullerene mediates proliferation and cardiomyogenic differentiation of adipose-derived stem cells via modulation of MAPK pathway and cardiac protein expression.

富勒烯通过调节 MAPK 通路和心脏蛋白表达来介导脂肪干细胞的增殖和心肌分化。

• 发表时间: 2016
• 作者: Hao, Tong;Zhou, Jin;Lü, Shuanghong;Yang, Boguang;Wang, Yan;Fang, Wancai;Jiang, Xiaoxia;Lin, Qiuxia;Li, Junjie;Wang, Changyong
• 通讯作者: Wang, Changyong

Unique mechanism of the interaction between honey bee toxin TPNQ and rKir1.1 potassium channel explored by computational simulations: insights into the relative insensitivity of channel towards animal toxins.

通过计算模拟探索蜜蜂毒素 TPNQ 和 rKir1.1 钾通道之间相互作用的独特机制：深入了解通道对动物毒素的相对不敏感性。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Hu, Jun;Qiu, Su;Yang, Fan;Cao, Zhijian;Li, Wenxin;Wu, Yingliang
• 通讯作者: Wu, Yingliang

Probing the effect of the non-active-site mutation Y229W in New Delhi metallo-β-lactamase-1 by site-directed mutagenesis, kinetic studies, and molecular dynamics simulations.

通过定点诱变、动力学研究和分子动力学模拟探讨新德里金属-β-内酰胺酶-1 中非活性位点突变 Y229W 的影响。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Chen, Jiao;Chen, Hui;Shi, Yun;Hu, Feng;Lao, Xingzhen;Gao, Xiangdong;Zheng, Heng;Yao, Wenbing
• 通讯作者: Yao, Wenbing

Two conserved arginine residues from the SK3 potassium channel outer vestibule control selectivity of recognition by scorpion toxins.

SK3 钾通道外前庭的两个保守精氨酸残基控制蝎毒素识别的选择性。

• 发表时间: 2013-05-03
• 作者: Feng, Jing;Hu, Youtian;Yi, Hong;Yin, Shijin;Han, Song;Hu, Jun;Chen, Zongyun;Yang, Weishan;Cao, Zhijian;De Waard, Michel;Sabatier, Jean;Li, Wenxin;Wu, Yingliang
• 通讯作者: Wu, Yingliang