Antipsychotic drug effects in limbic structures

项目概述：抗精神病药物（APDs）用于治疗精神分裂症，具有改善临床症状的潜力。由于apd确实需要时间才能充分发挥其治疗潜力，因此有人认为分子变化，即基因和蛋白质表达的改变，是其作用机制的重要组成部分。这些发现和假设表明(a)用apd治疗恢复了精神分裂症中受到干扰的过程或解剖底物，(b)基因表达改变参与了恢复。因此，分析apd治疗后相关解剖结构的基因表达变化可以为疾病、常规和非典型apd的作用机制提供有价值的信息，并可以为寻找新的治疗策略提供线索。在精神分裂症的相关解剖学基础中，边缘结构，特别是海马体和杏仁核是非常重要的。有一致的证据表明，精神分裂症伴随着海马体-杏仁核复合体的减少。这种减少与该疾病中较差的信息处理有关。在未用药的患者中也观察到异常，表明它们不是由治疗引起的。本研究将研究apd、氟哌啶醇和氯氮平慢性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，并以一种方式进行分析，以进一步了解将这些药物结合在一起的分子特性，以及将它们分开的特性。此外，我们将在这两种解剖结构中建立具有预测APD暴露价值的基因表达谱。该分析可作为未来药物发现目的的分析。相关性：使用最近开发的强大的分子工具，我们建议研究apd如何在精神分裂症中改变的大脑区域中起作用。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型抗精神病药物，以及(c)开发治疗精神分裂症的新方法。

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.