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大鼠可以作为具有独特特征和实用优势的精神分裂症的动物模型开发为具有基于基因的动物模型的独特特征和实用优势的动物模型，这些特征和实用优势是：1）基于基于遗传学的动物（即非诱导的），在Pretulse抑制作用（PPI）中，以及PPI的稳定缺陷，以及PPI的开始（PPI），以及开始的生命值（PPI），CC的cog and and and and and and and and。精神分裂症，2）用具有抗精神病药功效的药物逆转，3）能够区分具有不同临床特征的已建立的抗精神病药（例如，“典型的“'v v and typical”），4）对药物的敏感性，这些药物的敏感性，这些敏感性通过非传统机制（E.g.G.，neuroptiest）（neuroptiest）（neuroptiest）（neuroptiest）（neuroptiest）（neuroptiest），neuroptiesd（E.G.抗精神病药的最佳治疗作用，6）与精神分裂症类似的病理生理特征（例如D2受体升高），以及7）对于这些缺陷而言，明显的病因学（加压毒素缺乏症）对于这些缺陷而言尚未得到很好的研究，因此可以为Schizophrenia提供新的洞察力。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。 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. 第三组研究（特定目标3）将通过以下方式研究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-羟色胺受体的脑水平，以及3）检查中央加索素替代是否会恢复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。