RC3 Functional Neuroimaging of Alcoholism vulnerability: gultamate, reward, and

在CTNA-2中，我们发现，在货币激励延迟（MID）任务中，相对于FH-个体，FH+受试者在奖励机会出现时（奖励前景）增加了皮质纹状体网络的参与，但在奖励/惩罚延迟（奖励预期）或奖励出现时（完成奖励阶段）减少了同一网络的激活（见P3）。在进行Go/No-Go（GNG）任务期间，FH+中也观察到纹状体异常。在CTNA-3中，我们面临着将FH+中改变的皮质-纹状体功能与其基础神经生物学直接联系起来的挑战。目标一：本项目的第一个目的是确定是否增加NMDA-R功能有助于改变皮质纹状体活动与FH+状态。初步数据（见完整项目）支持目标#1的假设，建议美金刚40毫克。P.O.使FH+个体中与奖励预期相关的腹侧纹状体（VS）激活的缺陷正常化，但对FHN中的VS激活只有适度的影响。目的#2：该目的探索美金刚对GNG期间VS和前扣带回激活的影响。目标3：第三个项目的目标是关键的联系与FH+相关的皮质-纹状体功能改变的模式在成瘾过程中的初始步骤，巴甫洛夫条件反射。为此，完成目标#1的FH+个体也将在fMRI成像期间完成酒精提示反应性测试。目的#4：该探索性目的通过在FH+受试者中纳入PIT相关刺激（与FH-受试者相比）来检查MID的修改。 最后，这些受试者将是大学生，他们将进入由单独的NIAAA补助金支持的前瞻性2年随访（“BARCS”研究）。这个随访期将使CTNA能够探索奖励相关激活（MIDT），酒精巴甫洛夫条件反射（线索反应）和酒精PIT（通过核心电池评估）预测饮酒强度的可能性。将收集所有研究受试者的DNA，并通过遗传学核心研究编码图6中蛋白质的基因多态性的影响。

In CTNA-2, we showed that in a Monetary Incentive Delay (MID) task, FH+ subjects, relative to FH-individuals, had increased engagement of cortico striatal networks when the opportunity for reward presented itself (reward prospect), but reduced activation of this same network when rewards/punishments were delayed (reward anticipation) or when the reward was presented (consummatory reward phase) (see P3). Striatal abnormalities were also seen in FH+ during a Go/No-Go (GNG) task. In CTNA-3, we face the challenge of directly linking the altered cortical-striatal function in FH+ to its underlying neurobiology. Aim #1: The first aim of this project is to determine whether increased NMDA-R function contributes to alterations in cortico-striatal activity associated with FH+ status. Preliminary data (see full project) support the Aim #1's hypothesis by suggesting that memantine 40 mg. p.o. normalizes the deficits in ventral striatal (VS) activation associated with reward anticipation in FH+ individuals but has only modest effects on VS activation in FHN. Aim#2: This aim explores memantine effects on activation of VS and anterior cingulate during GNG. Aim #3: The third project aim is critical to linking the pattern of cortico-striatal functional alterations associated with FH+ to the initial step in the addiction process, Pavlovian Conditioning. To that end, FH+ individuals who complete Aim #1 also will complete alcohol cue reactivity testing during fMRI imaging. Aim #4: This exploratory aim examines a modification of the MID by inclusion of PIT-related stimuli in FH+ compared to FH- subjects. Lastly, these subjects will be college students who will enter a prospective 2-year follow-up supported by a separate NIAAA grant (the "BARCS" study). This follow-up period will enable CTNA to explore the possibility that reward-related activation (MIDT), alcohol Pavlovian conditioning (cue reactivity), and alcohol PIT (assessed via the Core Battery) predict the intensity of drinking over time. DNA will be collected on all study subjects and the impact of polymorphisms in the genes coding for the proteins in figure 6 will be explored via the Genetics Core.