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: 7086411
• 负责人: WILLIAM PERRY
• 金额: $ 37.72万
• 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/7086411
• 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）躁狂的特征，并为转化研究提供了行为靶点。该翻译项目的主要重点是评估躁狂BD患者和基于药理学挑战和基因工程技术的平行动物模型中三个抑制域的缺陷。广泛的动物数据以及最近的研究结果表明，BD与多巴胺转运蛋白（DAT）基因附近的遗传序列改变有关，这支持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措施，以促进我们对BD及其治疗的理解。该设计涉及在躁狂BD患者和DAT已被操纵的小鼠中进行的平行研究，其中DAT已被操纵，无论是安非他明（安非他明）还是遗传（DAT敲除和敲除小鼠）。具体而言，将评估三个领域的抑制缺陷：1.使用惊吓前脉冲抑制的感觉运动抑制受损; 2.在一个新的环境中使用适合物种的动态监测设备运动多动;和，3。运用运动反应的空间和时间模式的创新性非线性分析研究持续性。躁狂性BD住院患者将在入院时、高度症状时和抗躁狂和/或非典型抗精神病药物治疗期间纵向研究。正常对照受试者也将进行纵向研究，尽管未接受治疗。本申请的一个重要的创新方面是开发一个明确的人类类似物的开放领域，经典的啮齿动物行为范式用于评估多巴胺能精神兴奋剂的作用。用小鼠进行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以作为BD中抑制缺陷的模型，而DAT缺陷小鼠可以为抗躁狂剂的鉴定提供具有预测有效性的动物模型。跨物种的BD的核心特征的平行表征将使躁狂症的客观措施，可用于监测BD患者的治疗效果，并促进在啮齿动物中的BD同源预测模型的验证。这种临床前模型，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。