Inhibitory Deficits in Mania and Hyperdopaminiergic Mice

躁狂症和高多巴胺能小鼠的抑制缺陷

• 批准号: 6831257
• 负责人: WILLIAM PERRY
• 金额: $ 37.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-25 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831257
• 关键词: amphetamines; bipolar depression manic phase; central nervous system stimulants; clinical research; disease /disorder model; dopamine; dopamine transporter; genetically modified animals; human subject; laboratory mouse; neurotransmitter antagonist; sensorimotor system

DESCRIPTION (provided by applicant): Inhibitory deficits are characteristic of the mania of Bipolar Disorder (BD) and provide a behavioral target for translational research. The primary focus of this translational project is to assess deficits in three domains of inhibition in manic BD patients and in parallel animal models based on pharmacological challenges and gene engineering technology. Extensive animal data as well as recent findings linking BD to alterations in the genetic sequence in the vicinity of the dopamine transporter (DAT) gene support the basic hypothesis that the manic state involves a dysregulation of dopaminergic systems. This project uses and further develops cross-species measures that reflect abnormalities in dopaminergic systems to advance our understanding of BD and its treatment. The design involves parallel studies in manic BD patients and in mice in which the DAT has been manipulated either pharmacologically (amphetamine) or genetically (DAT knockdown and knockout mice). Specifically, inhibitory deficits in three domains will be assessed: 1. Impaired sensorimotor inhibition using prepulse inhibition of startle; 2. Motor hyperactivity in a novel environment using species-appropriate ambulatory monitoring devices; and, 3. Perseveration using innovative non-linear analyses of spatial and temporal patterns of motor responses. Manic BD inpatients will be studied at hospital admission, when highly symptomatic, and longitudinally during treatment with antimanic and/or atypical antipsychotic drugs. Normal comparison subjects will also be studied longitudinally, although in the absence of treatment. An important innovative aspect of this application is the development of an explicit human analog of the open field, the classic rodent behavioral paradigm used to assess dopaminergic psychostimulant effects. Experiments with mice will test the hypothesis that mutant mice lacking the normal complement of DAT might serve as a model of the inhibitory deficits in BD and that DAT-deficient mice might provide an animal model with predictive validity for the identification of antimanic agents. The parallel characterization of core features of BD across species will enable objective measures of mania that can be used to monitor treatment efficacy in BD patients and facilitate the validation of homologous predictive models of BD in rodents. Such preclinical models, and the human measures essential to their validation, are critical to the future discovery of novel treatments of this condition.

描述(由申请人提供)：抑制缺陷是双相情感障碍(BD)狂热的特征，并为翻译研究提供了一个行为靶点。这个翻译项目的主要焦点是评估躁狂BD患者的三个抑制领域的缺陷，以及基于药理学挑战和基因工程技术的平行动物模型。广泛的动物数据以及最近的发现将BD与多巴胺转运体(DAT)基因附近的遗传序列变化联系在一起，支持了躁狂状态涉及多巴胺能系统失调的基本假设。该项目使用并进一步开发了反映多巴胺能系统异常的跨物种测量方法，以促进我们对BD及其治疗的理解。这项设计涉及在躁狂的BD患者和DAT已经被药物(苯丙胺)或遗传(DAT基因敲除和敲除小鼠)操纵的小鼠中进行平行研究。具体地说，将评估三个领域的抑制缺陷：1.使用惊吓的脉冲前抑制来损害感觉运动抑制；2.使用适合物种的动态监测设备在新环境中的运动多动；以及3.使用对运动反应的空间和时间模式的创新的非线性分析来保持。躁狂型BD住院患者将在入院时进行研究，当有高度症状时，并在抗躁狂和/或非典型抗精神病药物治疗期间进行纵向研究。正常的比较对象也将被纵向研究，尽管在没有治疗的情况下。这一应用的一个重要创新方面是开发了一种显式的人类模拟开阔场地，这是用于评估多巴胺能心理刺激效应的经典啮齿动物行为范式。在小鼠身上的实验将检验这样的假设，即缺乏DAT正常补体的突变小鼠可能是BD抑制缺陷的模型，DAT缺陷小鼠可能为鉴定抗躁药提供具有预测有效性的动物模型。跨物种的BD核心特征的平行表征将使躁狂症的客观测量能够用于监测BD患者的治疗效果，并有助于验证啮齿动物BD的同源预测模型。这样的临床前模型，以及对其验证至关重要的人类措施，对于未来发现这种疾病的新治疗方法至关重要。