Dopaminergic Modulation of Immediate Reward Bias

立即奖励偏差的多巴胺能调节

• 批准号: 8265989
• 负责人: Mary K Kelm
• 金额: $ 3.69万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-05 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265989
• 关键词: Abstinence; Acute; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Amino Acids; Behavioral; Beverages; Brain; Catechol O-Methyltransferase; Characteristics; Cognitive; Communities; Complex; Consumption; Data; Decision Making; Development; Disease; Dopamine; Enzymes; Equilibrium; Functional Magnetic Resonance Imaging; Genotype; Human; Impulsivity; Incidence; Individual; Investigation; Knowledge; Laboratory Study; Lead; Magnetic Resonance Imaging; Mentors; Metabolism; Methyltransferase Gene; Neurobiology; Parietal; Parietal Lobe; Participant; Phenotype; Phenylalanine; Placebos; Play; Positioning Attribute; Prefrontal Cortex; Process; Recording of previous events; Regulation; Relapse; Relative (related person); Rewards; Role; Signal Transduction; Substance Use Disorder; Substance abuse problem; Supportive care; Techniques; Testing; Treatment outcome; Tyrosine; Variant; Work; alcohol abstinence; alcohol use disorder; base; clinically relevant; clinically significant; discounting; dopamine transporter; drug of abuse; frontal lobe; improved; inhibitor/antagonist; insight; neural circuit; neurobiological mechanism; neuromechanism; novel; preference; research study; tolcapone; trait

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.

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。一种可能减少复发发生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人中比那些没有酒精依赖史的人更常见。因此，这种对现在与以后的偏好，或立即奖励偏见，是酒精使用障碍的中间行为表型。这种中间表型被认为更适合调查，因为它们相对不那么复杂，并且与酒精使用障碍相比，可能在病因学上不那么异质。虽然最近的研究已经开始建立神经回路的基础立即奖励偏见，神经生物学机制，有助于这一临床上显着的行为特征仍有待充分调查。除了酒精滥用史，儿茶酚-O-甲基转移酶（COMT）基因的变异预测了现在与以后的偏好以及前额叶和后顶叶皮层的潜在大脑活动。COMT是一种负责多巴胺分解的酶，是大脑皮层多巴胺水平的主要调节因子。COMT基因中常见的功能变异导致酶具有高或低活性。COMT基因型导致高水平的COMT活性，因此多巴胺水平较低，与其他两种基因型相比，与更大的即时奖励偏差相关。这些数据表明，基线皮质多巴胺和个体对现在与以后的偏好之间存在反比关系。然而，目前尚不清楚基线多巴胺水平是否与多巴胺的瞬时波动相互作用，以改变即时奖励偏见和潜在的大脑活动。我们预测，在对照受试者和酒精依赖个体中，多巴胺的短暂波动将以COMT基因型依赖的方式影响立即奖励偏差和额顶叶活动。我们将通过两个补充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。在目标2中，我们将通过给予COMT抑制剂短暂升高多巴胺。在这两项研究中，参与者将在功能性磁共振成像期间完成现在/以后的决策任务，以测试急性多巴胺能操纵是否会改变立即奖励偏见和潜在的大脑活动，以及这种影响是否会受到COMT基因型或酒精使用史的调节。这是第一个研究检查冲动决策的药理学操纵的神经生物学基础。由于即时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，并改善寻求戒酒者的治疗效果。