Functional MRI of Biphasic Alcohol Effects

双相酒精效应的功能 MRI

• 批准号: 6956526
• 负责人: DAVID B NEWLIN
• 金额: $ 18.4万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6956526
• 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）已将酒精的更大的二相效应与酒精使用障碍（AUD）的易感性增加联系起来。拟议的研究将利用强大的大脑成像和分子遗传学技术来评估这种关系以及介导酒精反应的神经遗传学机制。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) 将双相局部脑血流 (rCBF) 和脑酒精水平与成瘾易感性基因型联系起来。这项研究将进一步了解大脑对酒精的反应及其与导致脆弱性的基因变异的关系。功能性；使用动脉自旋标记（ASL，Wang 等人，2004 年）测量 rCBF 和区域脑乙醇水平（rBEL）（改编自 Fein 和 Meyerhoff，2000 年）的磁共振成像（fMRI）实验将测试该模型的各个方面。惯用右手且无问题的饮酒者 (N = 32) 将在饮酒（双盲）酒精（0.375 或 075 g/kg）或安慰剂之前和之后参加 3 次功能磁共振成像检查。除了静脉血外，BEL 还将根据区域、时间（随时间进程）进行评估，并作为剂量的函数。我们预测，在上升的血液酒精曲线期间，左前额和腹侧纹状体 rCBF 会高于右前额和腹侧纹状体 rCBF、心动过速，并且双相酒精影响量表上的兴奋剂量表分数会更高（该个体峰值 BEL 的 50%，然后是 85%），并且在上升曲线期间，腹侧纹状体和腹侧纹状体 rCBF 总体会高于前额 Rcbf。我们预测下降曲线会出现相反的模式。参与者将根据成瘾相关基因组位点的基因型进行分层；一半的人具有高度遗传易感性，容易患上ADD；另一半将与高风险人群相匹配，其易感性较低。这种方法基于最近的研究结果，这些研究表明 ALDH 基因附近和其他基因组区域的分子标记与 AUD 和其他成瘾的发展有关。因此，本研究将测试 AUD 遗传传递中一种潜在的大脑通路——夸大的双相 rCBF 反应。