INHIBITORY DEFICITS IN HUMAN AND ANIMAL MODELS OF BIPOLAR DISORDER

双相情感障碍人类和动物模型的抑制缺陷

基本信息

批准号：
8432837
负责人：
MARK A GEYER
金额：
$ 46.04万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-25 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432837
关键词：
Abbreviations Acute Amphetamines Animal Disease Models Animal Model Animals Antimanic Agents Antipsychotic Agents Area Attention Attenuated Behavior Behavioral Behavioral Paradigm Behavioral inhibition Biological Markers Bipolar Disorder Brain Caffeine California Characteristics Chronic Cognitive Cognitive deficits Complex Decision Making Depressed mood Development Diagnostic Disease Disease remission Disinhibition Dopamine Dopamine Agonists Dose Drug effect disorder Environment Exhibits Family Functional disorder Funding Gambling Genetic Hamilton Rating Scale for Depression Human Hyperactive behavior Impairment Individual Inpatients Investigation Iowa Knock-out Life Link Lithium Manic Measures Mental Depression Methodology Modafinil Modeling Monitor Motor Activity Mus Neurobiology Neurotransmitters Participant Patients Pattern Performance Pharmaceutical Preparations Pharmacological Treatment Phase Phenotype Physiological Placebos Prefrontal Cortex Problem Solving Psychiatric Hospitals Regulation Relative (related person)Reporting Risk-Taking Rodent Schizophrenia Signal Detection Analysis Sorting - Cell Movement Stimulus Testing Thinking Translating Translations Treatment Protocols Wisconsin Work base cohort depressive symptoms dopamine transporter endophenotype experience functional outcomes hypomania inhibitor/antagonist meetings monoamine mouse model new technology novel novel therapeutic intervention performance tests prepulse inhibition programs public health relevance response therapy development trait translational approach translational study treatment effect vigilance

项目摘要

DESCRIPTION (provided by applicant): Bipolar Disorder (BD) is a severe psychiatric illness that is hallmarked by manic and depressive states. Inhibitory deficits are characteristic of BD and occur throughout the various phases of the illness. Problems with inhibition in people with BD may result in increased risk-taking behavior as well as difficulties in completing important tasks of daily living and complying with treatment. Consequently, studying profiles of disinhibition throughout the BD spectrum may elucidate traits of the disease that are present regardless of symptomatology. Furthermore, inhibitory deficits can be studied in both humans and animals using parallel methodology, thus contributing to the development of much-needed animal models of BD mania. During the past funding period, a novel technology was developed to study inhibitory deficits in humans (the human Behavioral Pattern Monitor: hBPM). Manic BD patients exhibited a "signature" pattern of inhibitory deficits that distinguished them from schizophrenia and nonpatient subjects. Furthermore, selective manipulation of the dopamine transporter in mice, either genetically (knockdown mice) or pharmacologically (GBR12909 administration), uniquely matched the inhibitory profile of manic BD patients. The present application seeks to test whether the inhibitory profile found among manic BD patients is specific to the manic state or persists during the other phases of BD, i.e., euthymic, depressed, and hypomanic states. Additionally, this investigation will examine multiple aspects of cognitive inhibition in a cross-species fashion. BD participants in various phases of their illness will be tested with the hBPM to measure hyperactivity and disinhibited exploration, the Conner's Continuous Performance Test to assess attentional inhibition, the Iowa Gambling Task to assess risk-taking inhibition, and the Wisconsin Card Sorting Task to assess perseverative inhibition. Mice will be tested in an analogous rodent BPM paradigm and in recently developed mouse versions of the three measures of cognitive inhibition listed above. In keeping with this program's cross-species translational approach, in which human studies inform animal investigations and animal studies inform the next logical step in the human work, an additional aim is to test whether pharmacological manipulations in healthy humans can mimic aspects of the manic BD profile. Thus, inhibitory functioning will be assessed in healthy non-patient subjects using dopamine agonist compounds (amphetamine and modafinil) and compared to a non-dopaminergic stimulant (caffeine) and placebo. These drugs will also be tested in the parallel mouse paradigms to examine the predictive validity of the rodent tasks. Finally, the BD mouse models will be tested at baseline and in response to antipsychotic and antimanic treatments using the cognitive and behavioral paradigms mentioned above. Studying human and parallel animal models of BD will facilitate the refinement of translational models, evaluate putative target endophenotypes, and identify behavioral biomarkers for use in proof-of-concept studies assessing the potential efficacy of novel therapeutic interventions for BD.

描述（由申请人提供）：双相情感障碍（BD）是一种严重的精神疾病，以躁狂和抑郁状态为特征。抑制缺陷是 BD 的特征，并且发生在疾病的各个阶段。双相情感障碍患者的抑制问题可能会导致冒险行为增加，以及难以完成重要的日常生活任务和遵守治疗。因此，研究整个 BD 谱系的去抑制特征可以阐明无论症状如何都存在的疾病特征。此外，可以使用平行方法在人类和动物中研究抑制缺陷，从而有助于开发急需的 BD 狂热动物模型。在过去的资助期间，开发了一项新技术来研究人类的抑制缺陷（人类行为模式监视器：hBPM）。躁狂双相情感障碍患者表现出抑制缺陷的“特征”模式，这将他们与精神分裂症和非患者受试者区分开来。此外，通过基因（基因敲低小鼠）或药理学（GBR12909给药）对小鼠多巴胺转运蛋白进行选择性操作，可以独特地匹配躁狂性双相情感障碍患者的抑制特征。本申请试图测试在躁狂 BD 患者中发现的抑制谱是否是躁狂状态特有的，还是在 BD 的其他阶段（即情绪正常、抑郁和轻躁狂状态）期间持续存在。此外，这项研究将以跨物种的方式检查认知抑制的多个方面。处于疾病不同阶段的 BD 参与者将接受 hBPM 测试，以测量多动症和去抑制探索，使用康纳连续表现测试来评估注意力抑制，使用爱荷华州赌博任务来评估冒险抑制，以及威斯康星州卡片分类任务来评估持续抑制。小鼠将在类似的啮齿动物 BPM 范式和最近开发的上述三种认知抑制测量的小鼠版本中进行测试。为了与该项目的跨物种转化方法保持一致，其中人类研究为动物调查提供信息，动物研究为人类工作的下一个逻辑步骤提供信息，另一个目的是测试健康人类的药理学操作是否可以模仿躁狂 BD 的各个方面轮廓。因此，将使用多巴胺激动剂化合物（安非他明和莫达非尼）在健康的非患者受试者中评估抑制功能，并与非多巴胺能兴奋剂（咖啡因）和安慰剂进行比较。这些药物还将在平行小鼠范例中进行测试，以检查啮齿动物任务的预测有效性。最后，将使用上述认知和行为范例对 BD 小鼠模型进行基线测试，并测试其对抗精神病药物和抗躁狂治疗的反应。研究 BD 的人类和平行动物模型将有助于完善转化模型，评估假定的目标内表型，并确定用于概念验证研究的行为生物标志物，以评估 BD 新型治疗干预措施的潜在功效。