ANTIPSYCHOTIC DRUG ACTION AFTER HIPPOCAMPAL DAMAGE

海马损伤后抗精神病药物的作用

• 批准号: 7960106
• 负责人: MARK Edward BARDGETT
• 金额: $ 16.96万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-22 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960106
• 关键词: Acute; Address; Adrenergic Receptor; Agonist; Alzheimer' s Disease; Animals; Antipsychotic Agents; Behavioral; Biomedical Research; Brain region; Chronic; Computer Retrieval of Information on Scientific Projects Database; Data; Disease; Drug effect disorder; Functional disorder; Funding; Gene Expression; Gene Proteins; Genes; Grant; Hippocampus (Brain); Institution; Learning; Lesion; Memory; Methods; Microarray Analysis; Modeling; Molecular; Motor Activity; Pharmacology; Prefrontal Cortex; Proteins; Rattus; Reporting; Research; Research Personnel; Resources; Schizophrenia; Short-Term Memory; Site; Source; United States National Institutes of Health; base; frontal lobe; improved; protein expression; receptor; synaptic function; transcription factor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction: Deformations and functional alterations of the hippocampus, a brain regions important in learning and memory, have been reported in disorders, such as schizophrenia and Alzheimer?s disease, that are commonly treated with antipsychotic drugs. However, it is unknown whether antipsychotic drugs can ameliorate the behavioral consequence of hippocampal dysfunction, or conversely, if hippocampal damage can undermine the behavioral and molecular pharmacology of antipsychotic drugs. The purpose of this project is to address these issues by using a rat model of excitotoxic hippocampal damage. Methods: The first aim of the grant has been to determine if and how acute or chronic antipsychotic drug treatment can reverse or reduce the effects of hippocampal damage on locomotor activity and spatial working memory. The second aim of the grant has been to determine if the effects of antipsychotic drug treatment on global gene expression are altered by hippocampal damage. The third aim has been to determine if and how hippocampal lesions alter the induction of transcription factors and other proteins by antipsychotic drug treatment. Results: Between July 2005 and February 2006, we have focused our research on two proteins that serve as receptors for antipsychotic drugs, the histamine3 (H3) and alpha2 (?2) adrenergic receptors. Our studies have found that antagonists for the former receptor can moderately improve spatial memory in rats with hippocampal damage, while agonists for the latter site do not improve spatial memory in such animals. These data served as the basis for an R15 application submitted in 2005 by the P.I.. (The application received a score of 199 and was not funded). We have also characterized the effects of hippocampal lesions on global gene expression in the prefrontal cortex using microarray technology. A number of genes related to synaptic function were found to be altered in the prefrontal cortex of lesioned animals. We will continue these lines of research as well as study the effects of antipsychotic drugs on gene and protein expression in the frontal cortex and other brain regions.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 简介：已经报道了通常用抗精神病药治疗的疾病（例如精神分裂症和阿尔茨海默氏病）的疾病（例如精神分裂症和阿尔茨海默氏病）的疾病中，海马的变形和功能改变是在学习和记忆中很重要的大脑区域。但是，尚不清楚抗精神病药能否改善海马功能障碍的行为后果，或者相反，如果海马损伤会破坏抗精神病药的行为和分子药理学。该项目的目的是通过使用兴奋性海马损伤的大鼠模型来解决这些问题。 方法：该赠款的第一个目的是确定急性或慢性抗精神药物治疗是否以及如何逆转或减少海马损伤对运动和空间工作记忆的影响。该赠款的第二个目的是确定抗精神病药治疗对全球基因表达的影响是否因海马损伤改变。第三个目的是确定海马病变是否以及如何通过抗精神病药治疗改变转录因子和其他蛋白质的诱导。 结果：在2005年7月至2006年2月之间，我们将研究集中在两种蛋白质上，这些蛋白质是抗精神病药的受体，组胺3（H3）和α2（？2）肾上腺素能受体。我们的研究发现，以前受体的拮抗剂可以中度改善具有海马损伤的大鼠的空间记忆，而后者部位的激动剂不能改善此类动物的空间记忆。这些数据是P.I .. 2005年提交的R15申请的基础（该申请的得分为199，没有资助）。我们还使用微阵列技术表征了海马病变对前额叶皮层中全球基因表达的影响。发现许多与突触功能有关的基因在病变的动物的前额叶皮层中发生了改变。我们将继续这些研究线，并研究抗精神病药对额叶皮质和其他大脑区域中基因和蛋白质表达的影响。