Functional MRI of Biphasic Alcohol Effects

描述(由申请人提供)：理论(Newlin&Thomson，1990)和经验证据(Newlin&Thomson，1991,1999)已将酒精更大的双相效应与酒精使用障碍(AUDS)的易感性增加联系起来。这项拟议的研究将使用强大的大脑成像和分子遗传学技术来评估这种关系，以及调节酒精反应的神经遗传学机制。具体地说，这项研究的长期目标是：(1)测试PI(Newlin)开发的关于可能介导对酒精的双相反应的大脑机制的模型；(2)确定酒精的脑药代动力学；以及(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。这项研究将进一步加深我们对酒精的大脑反应及其与导致易感性的基因变异的关系的理解。使用动脉自旋标记(ASL，Wang等人，2004)测量rCBF和局部脑酒精水平(Rbel)(改编自Fein&Meyerhoff，2000)的功能性磁共振成像(FMRI)实验将测试该模型的各个方面。右撇子没有问题的饮酒者(N=32)将在饮酒(双盲)酒精(0.375或075g/kg)或安慰剂之前和之后进行3次功能磁共振检查。除了静脉血外，还将对BEL进行区域性、临时性(在时间上)的评估，并作为剂量的函数进行评估。我们预测在血液酒精浓度上升曲线期间，左侧前额叶和腹侧纹状体rCBF大于右侧，心动过速，双相酒精效应量表上的刺激量表得分更高(分别为个体峰值BEL的50%和85%)，以及在上升曲线期间总体上大于前额叶Rcbf的腹侧纹状体和边缘rCBF。我们对下跌曲线的预测模式与之相反。参与者将根据他们在与成瘾相关的基因组基因座上的基因类型进行分层；一半将具有较高的遗传易感性，从而患上ADD；另一半，将与高危人群相匹配，将具有较低的易感性。这一方法是基于最近研究的结果，即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，这项研究将测试一种潜在的大脑通路--夸大的双相rCBF反应--在AUDS的遗传传播中。

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.