A Novel Animal Model of Relevance to Schizophrenia

与精神分裂症相关的新型动物模型

• 批准号: 7105105
• 负责人: DAVID FEIFEL
• 金额: $ 22.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-05 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105105
• 关键词: antipsychotic agents; arginine vasopressin; behavior test; behavioral /social science research tag; behavioral genetics; behavioral habituation /sensitization; disease /disorder etiology; disease /disorder model; dopamine antagonists; dopamine receptor; drug screening /evaluation; gene mutation; laboratory rat; memory disorders; mental disorder chemotherapy; model design /development; neurogenetics; nonhuman therapy evaluation; psychopathology; psychopharmacology; schizophrenia; sedative /hypnotic; sensory feedback; serotonin receptor; transfection /expression vector

DESCRIPTION (provided by applicant): Brattleboro (BB) rats have a single gene mutation causing abnormal vasopressin production. Preliminary findings from the PI's laboratory indicate that the BB rat may be developed as an animal model of schizophrenia-relevant information processing abnormalities that has unique strong features and practical advantages compared to existing animal models including: 1) genetically based (i.e., non-induced), stable deficits in prepulse inhibition (PPI), startle habituation, and cognitive function that are analogous to schizophrenia, 2) reversal by drugs with antipsychotic efficacy, 3) the ability to distinguish established antipsychotic drugs with distinct clinical profiles (e.g., "typical" versus "atypical"), 4) sensitivity to drugs that produce antipsychotic-like effects via non-traditional mechanisms (e.g., neuropeptides), 5) the ability to model the chronic time course associated with optimal therapeutic effects of antipsychotic drugs, 6) pathophysiology features that are analogous to schizophrenia (e.g., D2 receptor elevation), and 7) an apparent etiology (vasopressin deficiency) for these deficits that has not been well studied, and may therefore provide new insights into mechanisms contributing to schizophrenia. In a series of proposed experiments (Specific Aim 1) the sensitivity and specificity of the reversal of BB PPI deficits for drugs with antipsychotic efficacy will be further assessed. This will be done by testing several established typical and atypical antipsychotics, non-antipsychotic psychotropic drugs, as well as novel antipsychotics with non-conventional mechanisms (i.e., aripiprazole, amisulpride). A separate set of experiments (Specific Aim 2) will be aimed at characterizing the extent of the homology between BB rats and schizophrenia patients by assessing if the BB rat also exhibits antipsychotic-sensitive deficits in latent inhibition and social memory, whether their schizophrenia-like deficits are due to genetic versus parenting factors (via cross-fostering), and if they exhibit a schizophrenia-like ontological emergence. A third set of studies (Specific Aim 3) will investigate the mechanisms underlying BB PPI deficits by: 1) examining the effects of selective dopamine and serotonin antagonists, 2) measuring brain levels of dopamine and serotonin receptors, and 3) examining whether central vasopressin replacement restores PPI. The successful development of this animal model could significantly enhance the understanding of the underlying causes of schizophrenia-associated abnormalities and improve drug discovery.

描述（由申请人提供）：Brattleboro（BB）大鼠具有单个基因突变，导致异常加压素的产生。 PI的实验室的初步发现表明，与现有动物模型相比，与现有动物模型相比，BB大鼠可以作为与精神分裂症相关的信息处理异常开发，具有独特的特征和实用优势，与现有动物模型相比：1）基于遗传学模型（即）基于遗传的动物模型（即，不诱导的， ），稳定的预硫抑制作用（PPI），惊吓习惯和认知功能类似于精神分裂症，2）用具有抗精神病药疗效的药物逆转，3）能够区分具有独特临床特征的已建立抗精神病药物（例如，“例如” 4）对通过非传统机制产生抗精神病药样作用的药物的敏感性（例如，神经肽），5）5）能够模拟与抗毒性药物的最佳治疗效应相关的慢性时间过程的能力，6）类似于精神分裂症的病理生理特征（例如D2受体升高），以及7）对于这些缺陷的明显病因（加压素缺乏症），这些缺陷尚未得到很好的研究，因此可能为对精神分裂症有助于有助于精神分裂症的机制提供了新的见解。 在一系列提出的实验中（特定目标1）BB PPI缺陷对具有抗精神病毒疗效的药物的逆转的敏感性和特异性将得到进一步评估。这将通过测试几种已建立的典型和非典型抗精神病药，非抗精神病药精神药物以及具有非惯性机制的新型抗精神病药（即，阿里哌唑，Amisulpride）来完成。 单独的一组实验（特定目标2）将旨在通过评估BB大鼠是否还表现出抗精神病药敏感的潜在潜在抑制和社交记忆，是否表现出BB大鼠和精神分裂症患者之间同源性的程度缺陷是由于遗传因素与育儿因子（通过交叉培养）造成的，如果它们表现出类似精神分裂症的本体论出现。 第三组研究（特定目标3）将研究BB PPI缺陷的基础机制：1）检查选择性多巴胺和5-羟色胺拮抗剂的影响，2）测量多巴胺和5-羟色胺受体的大脑水平，以及3）检查中枢替代蛋白是否是否替换恢复PPI。 该动物模型的成功发展可以显着增强对精神分裂症相关异常的根本原因的理解，并改善药物发现。