Dopaminergic Modulation of Immediate Reward Bias

描述（由申请人提供）：对于幸运地戒酒的酒精依赖者，45%至75%的人至少会复发一次。一种潜在的减少复发的方法是研究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（“以后”），这在有酒精依赖史的个体中比在没有酒精依赖史的个体中更常见。这种现在对以后的偏好，或即时奖励偏见，因此是酒精使用障碍的中间行为表型。这种中间表型被认为更容易被研究，因为与酒精使用障碍相比，它们相对不那么复杂，而且可能在病因上不那么异质。虽然最近的研究已经开始建立即时奖励偏见背后的神经回路，但导致这种临床显著行为特征的神经生物学机制仍有待充分研究。除了酗酒史外，儿茶酚- o -甲基转移酶（COMT）基因的变异可以预测现在与以后的偏好以及前额叶和后顶叶皮层潜在的大脑活动。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剂。COMT基因中常见的功能变异会导致酶的活性高低。COMT基因型导致高水平的COMT活性，从而导致低水平的多巴胺，与其他两种基因型相比，它与更大的即时奖励偏差有关。这些数据表明，基线皮质多巴胺与个体对现在和以后的偏好之间存在反比关系。然而，尚不清楚基线多巴胺水平是否与多巴胺的短暂波动相互作用，从而改变即时奖励偏见和潜在的大脑活动。我们预测多巴胺的短暂波动将以COMT基因型依赖的方式影响对照受试者和酒精依赖个体的即时奖励偏差和额顶叶活动。我们将通过两个互补的实验来验证这一假设，这两个实验需要不同的多巴胺瞬时操作。在目标1中，我们将使用缺乏多巴胺合成所需前体的氨基酸饮料来急剧消耗多巴胺。在Aim 2中，我们将通过给予COMT抑制剂来短暂地升高多巴胺。在这两项研究中，参与者将在功能性磁共振成像期间完成一个Now/Later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见和潜在的大脑活动，以及这种影响是否会被COMT基因型或酒精使用史所缓和。这是第一个研究冲动决策的药理学操纵的神经生物学基础的研究之一。由于即时奖励偏见是酒精依赖个体的一个特征，这些结果可能会导致新的支持性疗法的发展，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. PUBLIC HEALTH RELEVANCE: These studies will provide the scientific community with information on the neurobiological mechanisms that contribute to impulsive decision making and the relationship between impulsive decision making and alcohol use disorders. Understanding the neural mechanisms of impulsive decision making may provide key insights into the neurobiology of alcohol use disorders and aid in the development of novel supportive therapies for these and related disorders.