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，FH+受试者相对于FH个体，当奖励机会出现时（奖励预期）皮质纹状体网络的参与增加，但当奖励/惩罚延迟（奖励预期）或奖励出现时（完成性奖励阶段）皮质纹状体网络的激活减少（见P3）。在Go/No-Go （GNG）任务中，FH+也出现纹状体异常。在cna -3中，我们面临着将FH+中皮质纹状体功能的改变与其潜在的神经生物学直接联系起来的挑战。目的1：该项目的第一个目的是确定NMDA-R功能的增加是否有助于与FH+状态相关的皮质纹状体活性的改变。初步数据（见完整项目）支持目标1的假设，表明美金刚40毫克p.o.使FH+个体与奖励预期相关的腹侧纹状体（VS）激活缺陷正常化，但对FHN的VS激活只有适度的影响。目的2：本目的探讨刚刚在GNG期间对VS和前扣带激活的影响。目标3：第三个项目目标对于将与FH+相关的皮质纹状体功能改变模式与成瘾过程的初始步骤巴甫洛夫条件反射联系起来至关重要。为此，完成目标1的FH+患者也将在fMRI成像期间完成酒精提示反应性测试。目的4：这个探索性目的是通过与FH-受试者相比，FH+受试者中包含pit相关刺激来检查MID的改变。

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.