Development of A Novel Animal Model of Tardive Dyskinesia

迟发性运动障碍新动物模型的开发

• 批准号: 7982453
• 负责人: Abraham Kovoor
• 金额: $ 36.76万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982453
• 关键词: Adult; Adverse effects; Affinity; Animal Model; Animals; Antipsychotic Agents; Applications Grants; Basal Ganglia; Biochemical; Brain; Brain region; Cardiovascular system; Chronic; Clinic; Clinical; Clinical Research; Corpus striatum structure; Data; Development; Dopamine D2 Receptor; Dopamine Receptor; Dose; Drug usage; Drug-Induced Dyskinesia; Etiology; Family; Functional disorder; Funding; Gene Deletion; Generations; Generic Drugs; Genes; Goals; Guanosine Triphosphate Phosphohydrolases; Haloperidol; Human; Hyperactive behavior; Incidence; Involuntary Movements; Knockout Mice; Lead; Learning; Mastication; Mediating; Mental disorders; Metabolic; Metabolic Diseases; Modeling; Molecular; Monkeys; Mouse Strains; Movement; Movement Disorders; Mus; National Institute of Mental Health; Neurologic; Neurons; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Plasma; Predisposition; Primates; Principal Investigator; Proteins; Psychotic Disorders; Publishing; RGS Proteins; Rattus; Receptor Signaling; Reporting; Research; Risk; Rodent; Rodent Model; Role; Schizophrenia; Severities; Signal Pathway; Signal Transduction; Structure; Suggestion; Symptoms; Syndrome; Tardive Dyskinesia; Testing; Time; Toxic effect; Validation; Viral; abnormal involuntary movement; base; expectation; improved; member; mouse model; nonhuman primate; novel; public health relevance; research study; response; treatment duration

DESCRIPTION (provided by applicant): The objective of this study is to validate the RGS9 knockout mouse as an animal model for tardive dyskinesia (TD). Antipsychotic drugs have revolutionized the treatment of schizophrenia, but an unfortunate side-effect is the development of TD, a debilitating hyperkinetic movement disorder. The liability of "typical" first-generation antipsychotic drugs to produce TD was recognized more than 50 years ago. Yet, very little of the underlying pathophysiology is understood other than that a necessary factor is the chronic blockade of D2- like dopamine receptors (D2R) expressed in the striatum. While the second-generation "atypical" drugs have a significantly reduced risk for producing TD, recently published results from clinical studies such as CATIE have emphasized their association with fatal cardiovascular and metabolic disorders and suggest a renewed role for the typical drugs in the pharmacotherapy of schizophrenia. However, the renewed use of the typical drugs depends critically on better understanding, managing and treating their potentially irreversible and serious side- effect, TD. A major impediment for understanding, managing and treating TD has been the lack of a practical animal model: the vacuous chewing rodent model and the more analogous primate model are extremely inefficient and expensive-large numbers of animals are treated for months to years to produce enough animals with TD-like symptoms. Thus the development of a useful, reliable and inexpensive mouse model of TD will be an important contribution to improving schizophrenia pharmacotherapy. The rationale for this study lies in data recently published by this principal investigator and others which suggest that a brain RGS protein, RGS9-2, is critical in the development of TD. They include the following observations: 1) RGS9-2 is expressed specifically in the striatum, an important component of the basal ganglia loop that controls movement and the brain structure that is critical in TD etiology, 2) RGS9-2 specifically colocalizes with D2R, the major target of antipsychotic drugs and specifically modulates D2R-activated striatal signaling pathways and 3) RGS9-2 knock-out mice developed hyperkinetic abnormal involuntary movements (AIMs) resembling TD after only three days of treatment with haloperidol, a typical antipsychotic drug. Here we propose to test the hypothesis that the RGS9 knockout mouse has etiological validity and models the clinical condition. An important etiological feature of TD is that it is produced by drugs that block D2R with high affinity (e.g. older typical antipsychotics), and lower affinity blockers (e.g. second generation antipsychotics) produce a lower incidence of TD. In addition once TD develops it is not easily reversed by cessation of drug-treatment. We will determine if these key clinical features of TD are preserved in the knockout mouse model. We will also test if exogenous viral-mediated striatal expression of RGS9-2 in the mouse model can suppress antipsychotic- induced AIMs. Such an experiment will help to confirm that altering RGS9-2 levels in adult striatum of the mouse model alters susceptibility to antipsychotic-induced AIMs and point to a strategy for treating TD. PUBLIC HEALTH RELEVANCE: A major debilitating and irreversible side-effect that limits the usefulness of drugs used to treat schizophrenia is the development of involuntary movements called tardive dyskinesia (TD). Very little is known about how TD occurs and how to treat it because of the lack of a convenient animal model. This application describes the development and validation of a mouse strain that lacks a functional gene for a protein called, RGS9-2, as a novel and convenient animal model for studying and learning to treat TD.

描述（由申请人提供）：本研究的目的是验证 RGS9 敲除小鼠作为迟发性运动障碍 (TD) 的动物模型。抗精神病药物彻底改变了精神分裂症的治疗，但一个不幸的副作用是发展为 TD（一种使人衰弱的多动性运动障碍）。 “典型的”第一代抗精神病药物导致 TD 的可能性早在 50 多年前就已被认识到。然而，除了纹状体中表达的 D2 样多巴胺受体 (D2R) 的慢性阻断这一必要因素之外，人们对潜在的病理生理学知之甚少。虽然第二代“非典型”药物显着降低了产生 TD 的风险，但最近发表的 CATIE 等临床研究结果强调了它们与致命的心血管和代谢疾病的相关性，并表明典型药物在精神分裂症药物治疗中的新作用。然而，典型药物的重新使用关键取决于更好地理解、管理和治疗其潜在的不可逆转的严重副作用 TD。理解、管理和治疗 TD 的一个主要障碍是缺乏实用的动物模型：空咀嚼啮齿动物模型和更相似的灵长类动物模型效率极低且昂贵——大量动物需要接受数月至数年的治疗才能产生足够多具有 TD 类似症状的动物。因此，开发有用、可靠且廉价的 TD 小鼠模型将为改善精神分裂症药物治疗做出重要贡献。这项研究的基本原理在于该首席研究员和其他人最近发表的数据，这些数据表明大脑 RGS 蛋白 RGS9-2 在 TD 的发展中至关重要。它们包括以下观察结果：1) RGS9-2 在纹状体中特异性表达，纹状体是控制运动和在 TD 病因学中至关重要的大脑结构的基底神经节环的重要组成部分，2) RGS9-2 与抗精神病药物的主要靶标 D2R 特异性共定位，并特异性调节 D2R 激活的纹状体信号通路，3) RGS9-2 敲除小鼠 在使用氟哌啶醇（一种典型的抗精神病药物）治疗仅三天后，患者就出现了类似于 TD 的多动性异常不自主运动 (AIM)。在这里，我们建议检验 RGS9 敲除小鼠具有病因学有效性并模拟临床状况的假设。 TD 的一个重要病因学特征是它是由高亲和力阻断 D2R 的药物（例如较老的典型抗精神病药）产生的，而亲和力较低的阻断剂（例如第二代抗精神病药）产生的 TD 发生率较低。此外，TD一旦发生，就很难通过停止药物治疗来逆转。我们将确定 TD 的这些关键临床特征是否在敲除小鼠模型中得以保留。我们还将测试小鼠模型中外源病毒介导的 RGS9-2 纹状体表达是否可以抑制抗精神病药物诱导的 AIM。这样的实验将有助于确认改变小鼠模型成年纹状体中的 RGS9-2 水平会改变对抗精神病药物诱导的 AIM 的易感性，并为治疗 TD 提供策略。 公共卫生相关性：限制用于治疗精神分裂症的药物的有效性的一个主要的使人衰弱且不可逆转的副作用是出现称为迟发性运动障碍（TD）的不自主运动。由于缺乏方便的动物模型，人们对 TD 如何发生以及如何治疗知之甚少。该申请描述了缺乏 RGS9-2 蛋白质功能基因的小鼠品系的开发和验证，该小鼠品系作为研究和学习治疗 TD 的新颖且方便的动物模型。