Dopaminergic Modulation of Immediate Reward Bias

描述(申请人提供)：对于有幸戒酒的酒精依赖者，45%至75%的人将至少复发一次。一种可能减少复发的方法是调查可能导致复发的行为特征的神经生物学。其中一个特征是倾向于选择较小的即时奖励(“现在”)，而不是较大的延迟奖励(“稍后”)，这在有酒精依赖史的人中比在没有酒依赖史的人中更常见。因此，这种现在对以后的偏好，或立即奖励偏向，是酒精使用障碍的一种中间行为表型。这种中间表型被认为更容易研究，因为与酒精使用障碍相比，它们相对不那么复杂，在病因上也可能不那么异质性。虽然最近的研究已经开始确定即时奖赏偏向背后的神经回路，但导致这种临床上重要的行为特征的神经生物学机制仍有待充分研究。除了酗酒史，儿茶酚-O-甲基转移酶(COMT)基因的变异还预示着现在与以后的偏好以及前额叶和后顶叶皮质潜在的大脑活动。COMT是一种负责分解多巴胺的酶，是大脑皮层多巴胺水平的主要调节器。COMT基因的一种常见功能变异导致一种酶的活性或高或低。与其他两种基因相比，COMT基因导致高水平的COMT活性，从而导致低水平的多巴胺，与更大的即刻奖赏偏向相关。这些数据表明，基线皮质多巴胺与个体对现在和将来的偏好之间存在着相反的关系。然而，目前尚不清楚基线多巴胺水平是否会与多巴胺的瞬时波动相互作用，从而改变即时的奖赏偏向和潜在的大脑活动。我们预测，在对照受试者和酒精依赖者中，多巴胺的瞬时波动将以COMT基因依赖的方式影响即时奖赏偏向和额顶活动。我们将通过两个互补的实验来验证这一假设，这两个实验需要对多巴胺进行不同的瞬时操作。在目标1中，我们将使用一种缺乏合成多巴胺所需前体的氨基酸饮料来急剧消耗多巴胺。在目标2中，我们将通过给予COMT抑制剂来短暂升高多巴胺。在这两项研究中，参与者将在功能磁共振成像期间完成一项现在/以后的决策任务，以测试急性多巴胺能操作是否会改变即时奖励偏向和潜在的大脑活动，以及这种影响是否受到COMT基因或酒精使用史的影响。这是研究冲动决策的药物操纵的神经生物学基础的首批研究之一。由于直接奖励偏见是酒精依赖者的一个特征，这些结果可能会导致开发新的支持性疗法，并改善寻求戒酒的人的治疗结果。

DESCRIPTION (provided by applicant): For alcohol-dependent individuals who are fortunate enough to become abstinent, 45% to 75% will relapse at least once. One way to potentially decrease the occurrence of relapse is to investigate the neurobiology of behavioral traits that may contribute to relapse. One such trait is the tendency to choose smaller immediate rewards ("Now") over larger delayed rewards ("Later"), which is more common among individuals with a history of alcohol dependence than among those without. This preference for Now versus Later, or immediate reward bias, is thus an intermediate behavioral phenotype for alcohol use disorders. Such intermediate phenotypes are thought to be more amenable to investigation, as they are relatively less complex and are likely to be less etiologically heterogeneous compared to alcohol use disorders. While recent studies have begun to establish the neural circuitry underlying immediate reward bias, the neurobiological mechanisms that contribute to this clinically significant behavioral trait remain to be fully investigated. In addition to alcohol abuse history, a variation in the catechol-O-methyltransferase (COMT) gene predicts both Now versus Later preference and underlying brain activity in the prefrontal and posterior parietal cortex. COMT is an enzyme responsible for the breakdown of dopamine and is the primary regulator of dopamine levels in the cortex. A common functional variation in the COMT gene results in an enzyme with either high or low activity. The COMT genotype that leads to high levels of COMT activity, and therefore low levels of dopamine, is associated with greater immediate reward bias relative to the other two genotypes. These data suggest there is an inverse relationship between baseline cortical dopamine and an individual's preference for Now versus Later. However, it is unknown whether baseline dopamine levels interact with transient fluctuations in dopamine to alter immediate reward bias and underlying brain activity. We predict that transient fluctuations in dopamine will affect immediate reward bias and fronto-parietal activity in a COMT genotype-dependent fashion in both control subjects and alcohol-dependent individuals. We will test this hypothesis with two complementary experiments that entail different transient manipulations of dopamine. In Aim 1, we will acutely deplete dopamine using an amino acid beverage deficient in the precursors required for dopamine synthesis. In Aim 2, we will transiently elevate dopamine by administering a COMT inhibitor. In both studies, participants will complete a Now/Later decision making task during functional magnetic resonance imaging to test whether acute dopaminergic manipulations change immediate reward bias and the underlying brain activity and whether such effects are moderated by COMT genotype or alcohol use history. This is one of the first studies to examine the neurobiological bases of pharmacological manipulation of impulsive decision making. Because immediate reward bias is a characteristic of alcohol-dependent individuals, these results could lead to the development of novel supportive therapies and improved treatment outcomes for people seeking abstinence.