ANIDEPRESSANTS--MOLECULAR AND CELLULAR ACTIONS

抗抑郁药——分子和细胞作用

基本信息

批准号：
6336678
负责人：
RONALD S. DUMAN
金额：
$ 18.09万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-23 至 2001-06-30
项目状态：
已结题

项目摘要

Depression is a devastating illness that has profound effects on our society. Although effective treatments have been available for over 35 years, approximately 30 percent of depressed patients are nonresponsive to available medications and the mechanism of action of antidepressant treatments (ADTs) remains largely known. Recent studies from our laboratory and other suggest that adaptations of the cAMP pathway could mediate the actions of ADTs. We have found that chronic administration of different types of ADTs, including norepinephrine (NE) and 5-HT selective reuptake inhibitors, increases the expression and function of the cAMP response element binding protein (CREB) in rat hippocampus. In addition, we have found that chronic ADTs increase the expression of brain derived neurotrophic factor (BDNF) in rat hippocampus, suggesting that it may be a target of CREB. The first specific aim of this Project is to test the hypothesis that CREB mediates the upregulation of BDNF in hippocampus using a combination of molecular and pharmacological tools. The second specific aim is to test the hypothesis that 5-HT receptors regulate CREB and BDNF. This is based on our finding that selective 5-HT reuptake inhibitors increase the expression of BDNF. Our preliminary studies demonstrate that expression of BDNF is differentially regulated by 5-HT2A, but not 5-HT1A, receptors in hippocampus and neocortex; this can be explained by the different electrophysiological effects of 5-HT2A receptors in these brain regions. The third specific aim of this Project is to test the hypothesis that upregulation of BDNF by ADTs results in regulation of the morphology and function of hippocampla neurons. Preliminary studies demonstrate that certain ADTs regulate growth-associated and cytoskeletal proteins and cause sprouting of neurons in hippocampus. The relevance of altered neuronal morphology and regulation of BDNF is highlighted by recent studies demonstrating that chronic stress causes atrophy of hippocampal neurons in rats and nonhuman primates and that the volume of hippocampus is decreased in some cases of depression. The proposed studies will utilized the collaborative expertise of our group, and will include Northern and Western blot, in situ hybridization, immunohistochemistry, and single cell labeling and recording, as well as a variety of mutant mice provided by the transgenic core facility. These studies outline a new area of research that will further our understanding of the molecular and cellular actions of ADTs, and could lead to more fast-acting and efficacious treatments for depression.

抑郁症是一种毁灭性的疾病，对我们的生活产生深远的影响社会。尽管已有有效的治疗方法 35 年来，大约 30% 的抑郁症患者对可用药物及其机制无反应抗抑郁治疗（ADT）的作用在很大程度上仍然已知。我们实验室和其他实验室的最新研究表明 cAMP 通路的适应可以介导 ADT。我们发现，长期服用不同的 ADT 类型，包括去甲肾上腺素 (NE) 和选择性 5-HT 再摄取抑制剂，增加大鼠 cAMP 反应元件结合蛋白 (CREB) 海马体。此外，我们发现慢性 ADT 增加脑源性神经营养因子的表达（BDNF）存在于大鼠海马体中，表明它可能是 CREB。该项目的第一个具体目标是测试 CREB 介导 BDNF 上调的假设海马体使用分子和药理学工具。第二个具体目标是测试假设 5-HT 受体调节 CREB 和 BDNF。这是基于我们的发现，选择性 5-HT 再摄取抑制剂增加 BDNF 的表达。我们的初步研究证明 BDNF 的表达受到以下因素的差异调节海马中的 5-HT2A 受体，但不是 5-HT1A 新皮质；这可以用不同的方式来解释 5-HT2A受体在这些大脑中的电生理效应地区。该项目的第三个具体目标是测试假设 ADT 上调 BDNF 会导致海马形态和功能的调节神经元。初步研究表明某些 ADT 调节生长相关蛋白和细胞骨架蛋白并引起海马体中神经元的萌芽。变更的相关性 BDNF 的神经元形态和调节最近的研究表明，长期压力会导致大脑萎缩大鼠和非人类灵长类动物的海马神经元在某些抑郁症病例中，海马体的体积会减少。拟议的研究将利用合作专业知识我们的小组，将包括原位北方印迹和西方印迹杂交、免疫组织化学和单细胞标记录音，以及由该公司提供的各种突变小鼠转基因核心设施。这些研究概述了一个新领域研究将进一步加深我们对分子和 ADT 的细胞作用，并可能导致更快速的作用和有效治疗抑郁症。