Functional MRI of Biphasic Alcohol Effects

双相酒精效应的功能 MRI

• 批准号: 7140198
• 负责人: DAVID B NEWLIN
• 金额: $ 23万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140198
• 关键词: alcohol dehydrogenase; alcoholism /alcohol abuse; bioimaging /biomedical imaging; biomarker; brain circulation; clinical research; disease /disorder proneness /risk; drug addiction; functional magnetic resonance imaging; genetic susceptibility; human subject; isozymes; neurochemistry; neuropharmacology; pharmacokinetics

DESCRIPTION (provided by applicant): Theory (Newlin & Thomson, 1990) and empirical evidence (Newlin & Thomson, 1991, 1999) have linked greater Diphasic effects of alcohol to heightened vulnerability to alcohol use disorders (AUDs). The proposed research will evaluate this relationship, as well as neurogenetic mechanisms that mediate alcohol response, using powerful brain imaging and molecular-genetic techniques. Specifically, the longterm goals of the research are to: (1) test a model developed by the PI (Newlin) concerning brain mechanisms that may mediate the biphasic response to alcohol; (2) determine brain pharmacokinetics of alcohol; and (3) relate biphasic regional cerebral blood flow (rCBF) and brain alcohol levels to addiction vulnerability genotypes. This research will further our understanding of brain responses to alcohol and their relationship to genetic variants that confer vulnerability. A functional; magnetic resonance imaging (fMRI) experiment using arterial spin labeling (ASL, Wang et al., 2004) to measure rCBF and regional brain ethanol levels (rBEL) (adapted from Fein & Meyerhoff, 2000) will test aspects of this model. Right-handed non-problematic drinkers (N = 32) will participate in 3 sessions with fMRI, before and after drinking (double-blind) alcohol (either 0.375 or 075 g/kg) or placebo. In addition to venous blood, BEL will be assessed regionally, temporally (over the time-course), and as a function of dose. We predict greater left than right prefrontal and ventral striatal rCBF, tachycardia, and greater Stimulant scale scores on the Biphasic Alcohol Effects Scale during the rising blood alcohol curve (50% then 85% of that individual's peak BEL), as well as overall greater ventral striatal and limbic rCBF than prefrontal Rcbf during the rising curve. We predict the opposite pattern for the falling curve. Participants will be stratified based on their genotypes at addiction-associated genomic loci; half will have high genetic vulnerability to develop an ADD; the other half, who will be matched to the high-risk group, will have low susceptibility. This approach is based on findings from recent studies implicating molecular markers in the vicinity of ALDH genes and at other genomic regions in the development of an AUD and other addictions. Therefore, this study will test one potential brain pathway-exaggerated biphasic rCBF responses-in the genetic transmission of AUDs.

描述（由申请人提供）：理论（Newlin & Thomson, 1990）和经验证据（Newlin & Thomson, 1991,1999）将酒精的双相效应与酒精使用障碍（AUDs）的易感性增加联系起来。拟议的研究将评估这种关系，以及介导酒精反应的神经遗传学机制，使用强大的脑成像和分子遗传学技术。具体来说，该研究的长期目标是：(1)测试PI （Newlin）开发的关于可能介导酒精双相反应的大脑机制的模型；(2)测定酒精的脑药代动力学；(3)将双相区域脑血流量（rCBF）和脑酒精水平与成瘾易感性基因型联系起来。这项研究将进一步加深我们对大脑对酒精的反应及其与遗传变异的关系的理解。一个功能;磁共振成像（fMRI）实验使用动脉自旋标记（ASL， Wang等人，2004年）来测量rCBF和区域脑乙醇水平（rBEL）（改编自Fein & Meyerhoff， 2000年）将测试该模型的各个方面。右撇子无问题饮酒者（N = 32）将在饮用（双盲）酒精（0.375或075 g/kg）或安慰剂之前和之后进行3次功能磁共振成像。除静脉血外，BEL还将被评估为区域性、暂时性（随时间变化）和剂量的函数。我们预测，在血液酒精浓度上升曲线期间，左前额叶和腹侧纹状体rCBF高于右前额叶和腹侧纹状体rCBF，心动过速和双相酒精效应量表上的兴奋剂评分更高（个体峰值BEL的50%和85%），以及在上升曲线期间，总体上腹侧纹状体和边缘rCBF高于前额叶rCBF。我们预测下降曲线的模式正好相反。参与者将根据成瘾相关基因组位点的基因型进行分层；一半的人有很高的遗传易感性，容易患上注意力缺陷多动症；另一半将与高危人群相匹配，易感性较低。这种方法是基于最近的研究结果，这些研究表明，在AUD和其他成瘾的发展过程中，ALDH基因附近和其他基因组区域的分子标记。因此，本研究将测试AUDs遗传传递中的一种潜在的脑通路-夸张的双相rCBF反应。