ANTIPSYCHOTIC DRUG ACTION AFTER HIPPOCAMPAL DAMAGE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。前言：海马体是大脑学习和记忆的重要区域，据报道，海马体的变形和功能改变在精神分裂症和阿尔茨海默病？S病等疾病中有报道，这些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区功能障碍的行为后果，或者相反，海马区损伤是否会破坏抗精神病药物的行为和分子药理学。这项资助的目的是通过使用兴奋性毒性海马区损伤的大鼠模型来解决这些问题。方法：赠款的第一个目标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区损害对运动活动和空间工作记忆的影响。这项拨款的第二个目的是确定抗精神病药物治疗对全球基因表达的影响是否会因海马体损伤而改变。第三个目标是确定海马区病变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：2005年7月至2006年2月，我们的研究集中在两种作为抗精神病药物受体的蛋白质上，组胺3(H3)和α2(？2)肾上腺素能受体。我们的研究发现，前一种受体的拮抗剂可以适度改善海马区损伤大鼠的空间记忆，而后一受体的激动剂不能改善这类动物的空间记忆。这些数据是P.I.在2005年提交的R15申请的基础。(该申请的得分为199分，没有获得资助)。我们还利用微阵列技术表征了海马区损伤对前额叶皮质整体基因表达的影响。一些与突触功能相关的基因在受损动物的前额叶皮质中被发现发生了改变。我们将继续这些研究，并研究抗精神病药物对额叶皮质和其他脑区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 grant 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.