Functional MRI of Biphasic Alcohol Effects

描述（由申请人提供）：理论（Newlin & Thomson，1990年）和经验证据（Newlin & Thomson，1991年，1999年）将酒精的更大双相效应与酒精使用障碍（AUD）的易感性增加联系起来。拟议中的研究将评估这种关系，以及介导酒精反应的神经遗传机制，使用强大的大脑成像和分子遗传技术。具体而言，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）确定酒精的大脑药代动力学;（3）将双相局部脑血流（rCBF）和大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遗传变异的关系。使用动脉自旋标记的功能性磁共振成像（fMRI）实验（ASL，Wang等人，2004）测量rCBF和局部脑乙醇水平（rBEL）（改编自Fein & Meyerhoff，2000）将测试该模型的各个方面。右撇子非问题饮酒者（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fMRI会议。除静脉血外，还将对BEL进行区域性、时间性（随时间推移）评估，并作为剂量的函数。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的rCBF大于右前额叶和腹侧纹状体的rCBF，心动过速，以及双相酒精效应量表上更大的刺激量表评分（50%，然后是85%的个人峰值BEL），以及在上升曲线期间，腹侧纹状体和边缘系统的rCBF总体上大于前额叶Rcbf。我们预测下降曲线的模式相反。参与者将根据他们在成瘾相关基因组位点的基因型进行分层;一半人将具有高遗传易感性，以发展ADD;另一半人将与高风险组相匹配，将具有低易感性。这种方法是基于最近的研究结果，这些研究结果涉及在AUD和其他成瘾的发展中ALDH基因附近和其他基因组区域的分子标记。因此，本研究将测试一个潜在的脑通路-夸大的双相rCBF反应-在遗传传递的AUDs。

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.