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）是一种受遗传影响的脑部疾病，经常与注意力相关。 缺陷/多动障碍（ADHD）是一种神经发育障碍，出现在儿童时期，并持续到 在30-45%的病例中成年。一种疾病的出现显著增加了另一种疾病的可能性， 并且患有AUD/ADHD共病的个体是具有挑战性的临床人群。这两种疾病的特点是 认知控制受损，这一过程部分受前额叶多巴胺（DA）信号的调节。 皮质（PFC）。精神兴奋剂是ADHD最常用的处方药，可提高PFC DA张力 并改善认知控制。然而，由于精神兴奋剂也会升高纹状体DA， 酒精的奖励和刺激作用，并减少其镇静作用，在个人共病 AUD/ADHD。非兴奋剂药物已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症状的影响托卡朋（TOLC），一种脑渗透性儿茶酚-O-甲基转移酶 （COMT）抑制剂批准用于治疗帕金森氏病，可能更有选择性地增强皮质， 而不是纹状体，DA释放，并已显示出改善动物认知控制和减少饮酒的前景。 模型TOLC的作用可能受到COMT中常见的单核苷酸多态性（SNP）的影响， 调节COMT功效。携带COMT val 158 met SNP的瓦尔等位基因的个体，其已被 与相对较高的COMT活性（因此，较低的PFC DA张力）相关，可能更有可能受益 TOLC治疗。我们的初步数据表明，TOLC减少了非寻求治疗者的饮酒 在患有AUD的个体中，并且在患有更多ADHD症状的个体中， COMT val等位基因携带者。 本项目旨在通过测试TOLC作为药物遗传学探针治疗AUD/ADHD的效果， 神经影像学和实验室为基础的AUD/ADHD措施和在自然环境中饮酒。一 将招募一组患有AUD/ADHD共病的未用药个体，并在受试者内进行安慰剂- 对照、双盲设计将用于测试TOLC和安慰剂对三组结果的影响：1）脑 与认知控制、选择性注意和酒精线索反应相关的激活; 2）酒精主观 在实验室中饮用标准饮料后的影响和风险决策;以及3）饮用超过六天 在自然环境中。此外，探索性目的将评价COMT val 158 met基因型 缓和TOLC对任何这些结果的影响。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共病个体的新治疗选择。

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.