A Novel Animal Model of Relevance to Schizophrenia

与精神分裂症相关的新型动物模型

基本信息

批准号：
7266954
负责人：
DAVID FEIFEL
金额：
$ 21.97万
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：
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/7266954
关键词：
Acute Adult Affinity Age Alzheimer&apos s Disease Amisulpride Animal Model Anti-Anxiety Agents Antidepressive Agents Antipsychotic Agents Base Pairing Behavior Birth Blood - brain barrier anatomy Brain Brattleboro Rats Chlorpromazine Chronic Clinical Clozapine Cognitive Cognitive deficits Computer information processing Condition Corpus striatum structure Development Diazepam Disease Dopamine Dopamine D2 Receptor Elevation Etiology Exhibits Fostering Functional disorder Gene Mutation Genes Genetic HTR2A gene Haloperidol Human Imipramine Individual Inherited Knowledge Laboratories Life Stress Long-Evans Rats Measures Mediating Memory Memory impairment Modeling Mutation Neurobiology Neuropeptides Neurotensin Noise Nucleus Accumbens Numbers Parenting behavior Patients Perphenazine Personal Satisfaction Pharmaceutical Preparations Physiologic pulse Play Preclinical Drug Evaluation Process Production Psychotropic Drugs Puberty Pulse taking Raclopride Range Rat Strains Rattus Reflex action Research Personnel Risperidone Rodent Role Schizophrenia Sensitivity and Specificity Sensory Series Serotonin Serotonin Antagonists Serotonin Receptor 5-HT2A Serotonin Receptors 5-HT-3 Site Specificity Stimulus Symptoms Testing Therapeutic Therapeutic Effect Thinking Time Vasopressins Viral Vector analog aripiprazole atypical antipsychotic base cognitive function conditioning drug discovery expectation improved insight interest millisecond monoamine neuropsychiatry novel olanzapine predictive modeling prepulse inhibition prevent pup quetiapine receptor research study response restoration social social attachment trait

项目摘要

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) 大鼠具有单一基因突变，导致加压素产生异常。 PI实验室的初步研究结果表明，BB大鼠可能被开发为精神分裂症相关信息处理异常的动物模型，与现有动物模型相比，其具有独特的强大功能和实用优势，包括：1）基于遗传的（即非诱导的）），类似于精神分裂症的前脉冲抑制（PPI）、惊吓习惯和认知功能的稳定缺陷，2）通过药物逆转抗精神病疗效，3）区分具有不同临床特征（例如“典型”与“非典型”）的现有抗精神病药物的能力，4）对通过非传统机制（例如神经肽）产生抗精神病样作用的药物的敏感性， 5) 能够模拟与抗精神病药物最佳治疗效果相关的慢性时间过程，6) 类似于精神分裂症的病理生理学特征（例如，D2 受体升高），7）这些缺陷的明显病因（加压素缺乏）尚未得到充分研究，因此可能为精神分裂症的机制提供新的见解。在一系列拟议的实验（具体目标 1）中，将进一步评估具有抗精神病功效的药物逆转 BB PPI 缺陷的敏感性和特异性。这将通过测试几种已确定的典型和非典型抗精神病药物、非抗精神病精神药物以及具有非常规机制的新型抗精神病药物（即阿立哌唑、氨磺必利）来完成。一组单独的实验（具体目标 2）旨在通过评估 BB 大鼠是否也表现出潜在抑制和社会记忆方面的抗精神病药物敏感性缺陷，以及它们是否患有精神分裂症样症状，来表征 BB 大鼠和精神分裂症患者之间的同源性程度。缺陷是由于遗传因素与养育因素（通过交叉培养）以及它们表现出类似精神分裂症的本体论出现而造成的。第三组研究（具体目标 3）将通过以下方式研究 BB PPI 缺陷的机制：1）检查选择性多巴胺和血清素拮抗剂的作用，2）测量多巴胺和血清素受体的大脑水平，以及 3）检查中枢加压素是否更换可恢复 PPI。这种动物模型的成功开发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。