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正式合作，以便通过专注于非临床表型来超越我们目前对ADHD病因概念化的局限性。非经典表型的选择是基于它们共同的病理生理，包括回路，这是符合“回路测试”的行为和药物解剖在动物模型和临床。这些ADHD表型以多巴胺能（DA）病理生理为核心特征，并在症状产生中具有共同的皮质-边缘谷氨酸能神经元（CGN）回路。每种表型都具有启发价值，不仅可以通过识别共同机制来理解ADHD“异常值”，还可以理解经典ADHD。我们假设一个这样的共享机制是关键的皮质-边缘通路的谷氨酸能价（Carlsson 2000）。我们提出铅暴露的ADHD表型作为确定DA基因型（DRD4, DRD5， DAT）与产生ADHD症状和损害的环境相互作用的原型。在我们的网络中，我们已经开发了行为/现象学和动物模型遗传决定因素水平的干预项目，以告知转化的“概念证明”临床试验。这项可行性试验将评估皮质-边缘去肾上腺素能（NE）释放药物阿托西汀的效应大小。现在可以使用直接DA激动剂/拮抗剂以及影响皮质边缘谷氨酸能神经元（CGN）回路的间接药物（如托莫西汀）对ADHD表型进行药理学解剖。该提案的主要优势包括：1)网络成员之间牢固、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，可以由此启动“概念证明”的药理学试验；3)一个具有良好特征和高度可用于ADHD-TS表型对映行为特征“电路测试”的动物模型；4)一个独特的机会来研究持续铅暴露队列的212名儿童的神经行为结果，因为队列达到了临床诊断为ADHD的典型时间（学龄）；5)检查与ADHD表型表达相关的da相关多态性的基因-环境相互作用，6)与儿科药理学研究单位（PPRU）基础设施、动物模型行为表型实验室和霍华德休斯生物信息学中心建立强大的网络外联系，以扩展Arrant的发现和“概念证明”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.