ANTIPSYCHOTIC DRUG ACTION AFTER HIPPOCAMPAL DAMAGE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 简介：海马体是学习和记忆的重要脑区，其变形和功能改变已被报道在精神分裂症和阿尔茨海默氏症等疾病中。这种疾病通常用抗精神病药物治疗。然而，目前尚不清楚抗精神病药物是否可以改善海马功能障碍的行为后果，或者相反，海马损伤是否可以破坏抗精神病药物的行为和分子药理学。本项目的目的是解决这些问题，通过使用大鼠模型兴奋性海马损伤。 研究方法：该补助金的第一个目的是确定急性或慢性抗精神病药物治疗是否以及如何逆转或减少海马损伤对运动活动和空间工作记忆的影响。该基金的第二个目的是确定抗精神病药物治疗对整体基因表达的影响是否会因海马损伤而改变。第三个目的是确定海马损伤是否以及如何改变抗精神病药物治疗对转录因子和其他蛋白质的诱导。 结果如下：在2005年7月和2006年2月之间，我们集中研究了两种作为抗精神病药物受体的蛋白质，组胺3（H3）和α 2（？2)肾上腺素能受体我们的研究发现，前者受体的拮抗剂可以适度改善海马损伤大鼠的空间记忆，而后者的激动剂不能改善这些动物的空间记忆。这些数据是P.I.于2005年提交的R15申请的基础。(The申请得到199分，没有得到资助）。我们还利用微阵列技术研究了海马病变对前额叶皮质整体基因表达的影响。研究发现，受损动物的前额叶皮质中许多与突触功能相关的基因发生了改变。我们将继续这些研究，并研究抗精神病药物对额叶皮层和其他大脑区域基因和蛋白质表达的影响。

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.