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

摘要 酒精使用障碍(AUD)是一种受基因影响的大脑疾病，经常与注意力共存-- 缺陷/多动障碍(ADHD)是一种神经发育障碍，从儿童时期开始出现，并持续到 30%-45%的病例为成年期。一种疾病的存在显著增加了另一种疾病的可能性， 患有AUD/ADHD的个体是一个具有挑战性的临床人群。这两种疾病的特点是 通过认知控制的损害，前额叶中的多巴胺(DA)信号部分调节的过程 皮层(PFC)。精神刺激剂，ADHD最常用的处方药，提高PFC DA音调 并提高认知控制能力。然而，由于精神刺激剂也会升高纹状体DA，它们可能会增强 酒精的奖赏和刺激作用，以及降低其在合并疾病患者中的镇静作用 AUD/ADHD。非兴奋剂药物已经在这一人群中进行了测试，但没有一种药物显示出效果 对AUD和ADHD症状都有影响。脑穿透性儿茶酚-O-甲基转移酶--Tolcapone (COMT)抑制剂被批准用于治疗帕金森氏病，可能更有选择性地增强皮质， 但不是纹状体，DA的释放，并在改善认知控制和减少动物饮酒方面显示出希望 模特们。TOLC的作用可能受到COMT中常见的单核苷酸多态(SNP)的影响 调节COMT疗效。携带COMT val158的Val等位基因的个体，已被 与相对较高的COMT活性相关(因此，较低的PFC DA音调)可能更有可能受益 来自TOLC治疗。我们的初步数据表明，TOLC减少了未寻求治疗的人的饮酒 患有AUD的人，在ADHD症状较多的人和 Comt Val等位基因携带者。 本项目旨在通过测试TOLC的疗效来评价TOLC作为一种治疗AUD/ADHD的药物遗传学探针 关于神经成像和以实验室为基础的AUD/ADHD措施以及在自然环境中饮酒。一个 将招募一组患有AUD/ADHD的未接受药物治疗的个体，并在受试者内部使用安慰剂- 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有关的激活；2)酒精主观 在实验室饮用标准饮料后的影响和风险决策；以及3)饮酒超过6天 在自然环境中。此外，一项探索性目标将评估COMT val158是否符合基因 缓解TOLC对上述任何结果的影响。这些目标的实现将潜在地促进大脑- 渗透性COMT抑制剂作为AUD/ADHD共病患者的新治疗选择。

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.