Antipsychotic drug effects in limbic structures

抗精神病药物对边缘结构的影响

基本信息

批准号：
7373664
负责人：
CHRISTINE L KONRADI
金额：
$ 28.51万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7373664
关键词：
Address Adverse effects Affect Aftercare Amygdaloid structure Anatomic structures Anatomy Antipsychotic Agents Area Attention Behavioral Binding Biological Assay Biological Process Brain Cell Nucleus Chronic Clinical Clozapine Complex Computer information processing Corpus striatum structure Data Deformity Development Disease Drug Exposure Drug effect disorder Drug usage Elements Emotional Exhibits Exposure to Family Functional disorder Future Gene Expression Gene Expression Profile Gene Expression Regulation Gene Family Gene Proteins Genes Goals Grouping Haloperidol Hippocampus (Brain)Human Light Molecular Molecular Profiling Pathologic Processes Patients Pattern Pharmaceutical Preparations Polymerase Chain Reaction Predictive Value Process Property Purpose Rattus Research Personnel Scanning Schizophrenia Structure Symptoms Testing Therapeutic Time Western Blotting atypical antipsychotic drug discovery frontal lobe insight interest novel novel strategies pre-clinical programs protein expression rat genome response tool

项目摘要

DESCRIPTION (provided by applicant): Project Summary: Antipsychotic drugs (APDs) are used to treat schizophrenia and they have the potential to ameliorate the clinical symptoms. Because APDs do take time to exhibit their full therapeutic potential, it has been suggested that molecular changes, i.e. altered gene and protein expression, are an important element of their mechanism of action. These findings and hypotheses imply that (a) treatment with APDs reinstates a process or anatomic substrate that is disturbed in schizophrenia, and (b) that gene expression changes are involved in the reinstatement. An analysis of gene expression changes in the relevant anatomical structures after treatment with APDs could therefore provide valuable information about the disease, the mechanism of action of both conventional and atypical APDs, and it could provide leads in the search for novel treatment strategies. High amongst the relevant anatomical substrates in schizophrenia are limbic structures, particularly the hippocampus and the amygdala. It has been shown consistently that schizophrenia is accompanied by reductions in the hippocampus-amygdala complex. This reduction is correlated with poorer information processing in the disorder. The abnormalities have also been observed in drug-naive patients, indicating that they are not caused by the treatment. The present proposal will investigate gene expression patterns in the hippocampus and the amygdala of rats after chronic treatment with the APDs, haloperidol and clozapine. Both drugs will be used at three different concentrations in independent groups of rats, and analyzed in a manner to further our understanding of the molecular properties that unite these drugs, as well as properties that separate them. Furthermore, we will establish a gene expression profile in both anatomic structures that has predictive value for APD exposure. This profile can serve as an assay for future drug-discovery purposes. Relevance: Using recently developed, powerful molecular tools, we propose to investigate how APDs act in brain areas that are altered in schizophrenia. The information gained can be used to (a) understand some of the underlying pathophysiology in schizophrenia, (b) develop more useful assays to scan novel drugs for antipsychotic properties, and (c) develop novel approaches to the treatment of schizophrenia.

描述（由申请人提供）：项目摘要：抗精神病药物（APD）用于治疗精神分裂症，有可能改善临床症状。由于 APD 确实需要时间才能发挥其全部治疗潜力，因此有人认为分子变化，即基因和蛋白质表达的改变，是其作用机制的一个重要因素。这些发现和假设意味着（a）APD 治疗可恢复精神分裂症中受到干扰的过程或解剖基质，以及（b）基因表达变化参与恢复。因此，对 APD 治疗后相关解剖结构中基因表达变化的分析可以提供有关疾病、传统和非典型 APD 的作用机制的有价值的信息，并且可以为寻找新的治疗策略提供线索。精神分裂症的相关解剖基础中最重要的是边缘结构，特别是海马体和杏仁核。研究一致表明，精神分裂症伴随着海马-杏仁核复合体的减少。这种减少与疾病中较差的信息处理有关。在未接受药物治疗的患者中也观察到了这些异常，表明它们不是由治疗引起的。本提案将研究经过 APD、氟哌啶醇和氯氮平长期治疗后大鼠海马和杏仁核的基因表达模式。这两种药物将以三种不同的浓度在独立的大鼠组中使用，并以进一步我们对这些药物的分子特性以及分开它们的特性的理解的方式进行分析。此外，我们将在两个解剖结构中建立基因表达谱，对 APD 暴露具有预测价值。该概况可以作为未来药物发现目的的分析方法。相关性：利用最近开发的强大分子工具，我们建议研究 APD 如何在精神分裂症改变的大脑区域中发挥作用。获得的信息可用于（a）了解精神分裂症的一些潜在病理生理学，（b）开发更有用的检测方法来扫描新药物的抗精神病特性，以及（c）开发治疗精神分裂症的新方法。