ADHD Phenotype Network: Animal Model to Clinical Trial

描述（由申请人提供）：我们的网络小组寻求正式的神经科学家，遗传学家，药理学家，儿科医生和儿童精神病学家的合作，以超越我们目前的ADHD病因学概念的局限性，专注于非临床表型。非经典表型的选择是基于其共同的病理生理学，涉及电路，这是经得起“电路测试”的行为和药理学解剖的动物模型以及临床。这些ADHD表型涉及多巴胺能（DA）病理生理学作为核心特征，并且在症状产生中共享共同的皮质-边缘核神经元（CGN）回路。每一种表型都有独特的价值，不仅可以理解ADHD的“离群值”，还可以通过识别共同的机制来理解经典ADHD。我们假设的一个共同机制是关键皮质-边缘系统通路的多巴胺能效价（Carlsson 2000）。铅暴露的ADHD表型，我们建议作为一个原型，以确定DA基因型（DRD 4，DRD 5，DAT）和环境的相互作用，产生ADHD症状和损害。在我们的网络中，我们已经在行为/现象学和动物模型遗传决定因素水平上开发了干预项目，以告知翻译的“概念验证”临床试验。这项可行性试验将估计皮质-边缘去甲肾上腺素能（NE）释放药物托莫西汀的效应量。现在可以使用直接DA激动剂/拮抗剂以及影响皮质-边缘系统神经元（CGN）回路的间接药物（如托莫西汀）对ADHD表型进行药理学分析。该提议的主要优势包括：1）网络成员之间强有力的、持续的合作关系; 2）关于临床实践中遇到的非经典ADHD表型的新颖且可测试的假设，由此可以启动“概念验证”药理学试验; 3）动物模型，其被充分表征并且高度可用于ADHD-TS表型的对足行为特征的“电路测试”; 4）一个独特的机会，研究一个正在进行的铅暴露队列的212名儿童的神经行为结果，因为队列达到的时间（学龄）当ADHD的临床诊断通常发生时; 5）与ADHD表型表达相关的DA相关多态性的基因-环境相互作用的检查，以及6）与儿科药理学研究单位（PPRU）基础设施的强大的外部网络联系，一个动物模型行为表型实验室，和一个霍华德休斯生物信息学中心，以扩大Arrant的发现和“概念验证”试验。

DESCRIPTION (provided by applicant): Our network group seeks to formalize a collaboration of neuroscientists, geneticist, pharmacologists, pediatricians, and child psychiatrist so as to transcend the limitations of our present conceptualization of ADHD etiology by concentrating on non-clinical phenotypes. Non-classical phenotypes were chosen based on their shared pathophysiology involving circuitry which is amenable to "circuit-testing" of behavior and pharmacologic dissection in animal models as well as the clinic. These ADHD phenotypes involve dopaminergic (DA) pathophysiology as a core feature, and share common cortical-limbic glutamatergic neuronal (CGN) circuitry in symptom generation. Each phenotype has heuritic value to bring an understanding not only to ADHD "outliers" but for classical ADHD through the identification of shared mechanisms. One such shared mechanism we hypothesize is the glutamatergic valence of key cortical-limbic pathways (Carlsson 2000). The lead-exposed ADHD phenotype we propose as a prototype for determining the interaction of DA genotype (DRD4, DRD5, DAT) and environment producing ADHD symptoms and impairment. In our network, we have developed interposing projects at the behavioral/phenomenologic and animal model-genetic determinant levels to inform a translational "proof of concept" clinical trial. This feasibility trial will estimate effect sizes for the cortical-limbic noradrenergic (NE) releasing drug, atomoxetine. Pharmacologic dissection of ADHD phenotypes is now possible using direct DA agonists/antagonists as well as indirect agents impacting cortical-limbic glutamatergic neuronal (CGN) circuitry like atomoxetine. Major strengths of this proposal include: 1) Strong, ongoing collaborative relationships between network members; 2) novel and testable hypothesis regarding non-classical ADHD phenotypes encountered in clinical practice from which "proof of concept" pharmacologic trials can be initiated; 3) an animal model that is well characterized and highly exploitable for "circuit-testing" of antipodal behavioral features of the ADHD-TS phenotype; 4) a unique opportunity to study the neurobehavioral outcomes of an ongoing lead-exposed cohort of 212 children as the cohort reaches the time (school-age) when a clinical diagnosis of ADHD typically occurs; 5) examination of gene-environment interactions with DA-associated polymorphisms linked to ADHD phenotype expression, and 6) strong, extra-network linkages with the pediatric pharmacologic research units (PPRU) infrastructure, an animal model behavioral phenotyping laboratory, and a Howard Hughes Bioinformatics Center to expand on Arrant findings and "proof of concept' trials.