ANIDEPRESSANTS--MOLECULAR AND CELLULAR ACTIONS

抗抑郁药——分子和细胞作用

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/6336678
• 关键词: antidepressants; antisense nucleic acid; cAMP response element binding protein; cell biology; dentate gyrus; depression; gel mobility shift assay; genetically modified animals; genotype; glutamate receptor; hippocampus; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; messenger RNA; molecular biology; neurotrophic factors; northern blottings; oligonucleotides; phosphodiesterase inhibitors; psychopharmacology; receptor expression; serotonin inhibitor; serotonin receptor; western blottings

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 社会。 尽管有效的治疗可用于 超过35年，大约30％的抑郁症患者是 对可用药物的无反应和机制 抗抑郁治疗的作用（ADT）在很大程度上仍然是 已知。我们的实验室的最新研究表明 训练营的改编可以调解 adts。 我们发现长期给药不同 ADT的类型，包括去甲肾上腺素（NE）和5-HT选择性 再摄取抑制剂，增加了 大鼠的cAMP响应元件结合蛋白（CREB） 海马。 此外，我们发现慢性ADT 增加脑衍生神经营养因子的表达 （BDNF）在大鼠海马中，表明它可能是 克里布。 该项目的第一个具体目的是测试 Creb介导BDNF的上调的假设 海马使用分子和 药理工具。 第二个具体目的是测试 假设5-HT受体调节CREB和BDNF。这是 根据我们的发现，有选择性的5-HT再摄取抑制剂 增加BDNF的表达。 我们的初步研究 证明BDNF的表达受到差异调节 5-HT2A，但不是5-HT1A，是海马中的受体和 Neocortex;这可以用不同的 这些大脑中5-HT2A受体的电生理效应 地区。 该项目的第三个具体目的是测试 假设ADTS上调BDNF导致 调节河马的形态和功能 神经元。 初步研究表明某些ADT 调节生长相关和细胞骨架蛋白，并引起 海马中神经元的发芽。 改变的相关性 BDNF的神经元形态和调节。 最近的研究表明，慢性应激会导致 大鼠和非人类灵长类动物的海马神经元， 在某些情况下，海马体积减少。 拟议的研究将利用 我们的小组，并将包括北部和西部印迹，原位 杂交，免疫组织化学和单细胞标记和 记录，以及由 转基因核心设施。 这些研究概述了一个新领域 研究将进一步理解分子和 ADT的细胞作用，可能会导致更快的作用和 抑郁症的有效治疗方法。