COMT inhibition as a potential therapeutic target among individuals with comorbid Alcohol Use Disorder and Attention-Deficit/Hyperactivity Disorder

COMT 抑制作为共病酒精使用障碍和注意力缺陷/多动障碍患者的潜在治疗靶点

• 批准号: 10597530
• 负责人: JOSEPH P. SCHACHT
• 金额: $ 33.09万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597530
• 关键词: Acceleration; Achievement; Adult; Advanced Development; Alcohol consumption; Alcohols; Alleles; Animal Model; Animals; Attention; Attention deficit hyperactivity disorder; Behavior; Brain; Brain Diseases; Catechol O-Methyltransferase; Child; Childhood; Clinical; Cognitive; Consumption; Corpus striatum structure; Crossover Design; Cues; Data; Decision Making; Disease; Dopamine; Dose; Double-Blind Method; Drug Prescriptions; Enrollment; Environment; Evaluation; FDA approved; Funding; General Population; Genetic Carriers; Genotype; Homozygote; Human; Image; Impairment; Individual; Laboratories; Measures; Mediating; Methods; National Institute on Alcohol Abuse and Alcoholism; Neurodevelopmental Disorder; Outcome; Parkinson Disease; Pharmaceutical Preparations; Pharmacogenetics; Placebo Control; Placebo Effect; Placebos; Population; Prefrontal Cortex; Process; Rewards; Sedation procedure; Self-control as a personality trait; Signal Transduction; Single Nucleotide Polymorphism; Symptoms; Synapses; Testing; Time; alcohol comorbidity; alcohol cue; alcohol reward; alcohol use disorder; cognitive control; comorbidity; cue reactivity; design; dopamine transporter; drinking; heavy drinking young adult; improved; inhibitor; interest; neuroimaging; new therapeutic target; outcome prediction; placebo group; psychostimulant; recruit; selective attention; stimulant use; therapeutic target; tolcapone

ABSTRACT Alcohol Use Disorder (AUD) is a genetically influenced brain disease that is frequently comorbid with Attention- Deficit/Hyperactivity Disorder (ADHD), a neurodevelopmental disorder that arises in childhood and persists into adulthood in 30-45% of cases. The presence of one disorder significantly increases the likelihood of the other, and individuals with comorbid AUD/ADHD are a challenging clinical population. Both disorders are characterized by impairments in cognitive control, a process regulated in part by dopamine (DA) signaling in the prefrontal cortex (PFC). Psychostimulants, the most commonly prescribed medications for ADHD, elevate PFC DA tone and improve cognitive control. However, because psychostimulants also elevate striatal DA, they may potentiate alcohol’s rewarding and stimulating effects, and reduce its sedating effects, among individuals with comorbid AUD/ADHD. Non-stimulant medications have been tested in this population, but none has demonstrated effects on both AUD and ADHD symptoms. Tolcapone (TOLC), a brain-penetrant catechol-O-methyltransferase (COMT) inhibitor approved for the treatment of Parkinson’s disease, may more selectively potentiate cortical, but not striatal, DA release, and has shown promise in improving cognitive control and reducing drinking in animal models. TOLC’s effects may be influenced by a common single nucleotide polymorphism (SNP) in COMT that regulates COMT efficacy. Individuals who carry the val allele of the COMT val158met SNP, which has been associated with relatively higher COMT activity (and thus, lower PFC DA tone), may be more likely to benefit from TOLC treatment. Our preliminary data indicate that TOLC reduces drinking among non-treatment-seeking individuals with AUD, and does so to a greater extent among those with more ADHD symptoms and among COMT val-allele carriers. This project aims to evaluate TOLC as a pharmacogenetic probe for AUD/ADHD treatment, by testing its effects on neuroimaging and laboratory-based AUD/ADHD measures and on drinking in the natural environment. A group of unmedicated individuals with comorbid AUD/ADHD will be recruited, and a within-subjects, placebo- controlled, double-blind design will be used to test TOLC and placebo effects on three sets of outcomes: 1) brain activation associated with cognitive control, selective attention, and alcohol cue reactivity; 2) alcohol subjective effects and risky decision-making after consumption of a standard drink in the lab; and 3) drinking over six days in the natural environment. Additionally, an exploratory aim will evaluate whether COMT val158met genotype moderates TOLC effects on any of these outcomes. Achievement of these aims will potentially advance brain- penetrant COMT inhibitors as a new treatment option for individuals with comorbid AUD/ADHD.

抽象的 酒精使用障碍 (AUD) 是一种受遗传影响的脑部疾病，经常与注意力不集中共存。 缺陷/多动障碍 (ADHD)，一种出现于儿童期并持续到成年的神经发育障碍 30-45% 的病例在成年后出现一种疾病的可能性会显着增加。 患有 AUD/ADHD 的患者是一个具有挑战性的临床人群，这两种疾病都有其特点。 认知控制受损，这一过程部分受前额叶多巴胺 (DA) 信号调节 精神兴奋剂是治疗多动症最常用的药物，可提高 PFC DA 音调。 然而，由于精神兴奋剂也会提高纹状体 DA，因此它们可能会增强。 在患有共病的个体中，酒精的奖励和刺激作用，并减少其镇静作用 AUD/ADHD 已在该人群中进行了测试，但没有显示出效果。 托卡朋 (TOLC) 是一种脑渗透性儿茶酚-O-甲基转移酶。 (COMT) 抑制剂被批准用于治疗帕金森病，可能更有选择性地增强皮质、 但纹状体中不存在 DA 释放，并且在改善动物认知控制和减少饮酒方面显示出希望 TOLC 的效果可能受到 COMT 中常见的单核苷酸多态性 (SNP) 的影响。 调节 COMT 功效的个体携带 COMT val158met SNP 的 val 等位基因。 与相对较高的 COMT 活动（因此，较低的 PFC DA 音调）相关，可能更有可能受益 我们的初步数据表明，TOLC 减少了不寻求治疗的人的饮酒情况。 患有 AUD 的个体，并且在具有更多 ADHD 症状的人和 COMT val 等位基因携带者。 该项目旨在通过测试其效果来评估 TOLC 作为 AUD/ADHD 治疗的药物遗传学探针 神经影像学和基于实验室的 AUD/ADHD 测量以及自然环境中的饮酒 A。 将招募一组患有 AUD/ADHD 共病的未接受药物治疗的个体，并在受试者中进行安慰剂治疗 受控双盲设计将用于测试 TOLC 和安慰剂对三组结果的影响：1) 大脑 与认知控制、选择性注意和酒精提示反应相关的激活 2) 酒精主观； 在实验室饮用标准饮料后的影响和危险决策；3) 饮酒超过六天； 此外，探索性目标将评估 COMT val158met 基因型。 调节 TOLC 对任何这些结果的影响。这些目标的实现将有可能促进大脑的发展。 渗透性 COMT 抑制剂作为 AUD/ADHD 共病患者的新治疗选择。