MONOAMINE INTERACTIONS AND ANTIDEPRESSANT DRUGS

单胺相互作用和抗抑郁药物

• 批准号: 6089085
• 负责人: Michelle E Page
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-05 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6089085
• 关键词: amines; antidepressants; behavior test; behavioral /social science research tag; drug administration rate /duration; drug interactions; frontal lobe /cortex; hippocampus; laboratory rat; microdialysis; norepinephrine; psychopharmacology; serotonin; serotonin inhibitor; stressor

DESCRIPTION (adapted from applicant's abstract): Much evidence exists to support the interrelationship between dysfunction of the monoamine neurotransmitter systems, stress and the onset of depressive illness. For years research suggested disruption of the noradrenergic response to stress as the predisposing factor in depression. This was based on animal studies describing depletion of norepinephrine (NE) in response to severe stressors coupled with clinical evidence that many compounds which increased NE were effective in reducing the symptoms associated with this disorder. Due in part to the many adverse side effects associated with tricyclic antidepressants, newer more selective compounds were developed and the success of the serotonin (5-HT) selective reuptake inhibitors (SSRIs) as antidepressants shifted the focus of the field to re-examine the role of serotonin in depression. This is the most widely prescribed class of antidepressants today. However, there is a paucity in the knowledge of how all antidepressants exert therapeutic action. A continued effort to understand the mechanism of action of antidepressants is now focused on the interrelationship of NE and 5-HT. The proposed research program will attempt to provide evidence for important interactions between these two neurotransmitter systems that may help to explain the ability of diverse pharmacological agents to exert similar clinical benefits. Specifically, studies will examine the hypothesis that even though selective neuronal transporter inhibitors may act specifically when administered acutely, they will have indirect actions on other systems following chronic administration. This ability to alter multiple monoamine systems after chronic drug administration may account for the delay in therapeutic effects. Additionally, a nonselective reuptake inhibitor, venlafaxine, will be compared with the NE-selective inhibitor reboxetine and the 5-HT selective reuptake inhibitor fluoxetine to determine whether there is a basis for nonselective monoamine reuptake inhibition to confer greater therapeutic benefits. In addition, experiments will be performed to examine the hypothesis that both 5-HT and NE systems mediate behavioral responses to swim stressor. Furthermore, the impact of chronic antidepressant treatment on the behavioral responses and neurochemical effects associated with the swim stressor will be explored. The results of the proposed studies will provide insight into neuronal adaptations of two monoamine neurotransmitter systems that have been implicated in depression and be useful in the development of therapeutic agents for the treatment of depression.

描述（改编自申请人的摘要）：存在大量证据 支持单胺功能障碍之间的相互关系 神经递质系统、压力和抑郁症的发作。多年来 研究表明，去甲肾上腺素能对压力的反应被破坏 抑郁症的诱发因素。这是基于动物研究描述的 去甲肾上腺素（NE）因严重压力而消耗，加上 临床证据表明，许多增加 NE 的化合物对 减少与这种疾病相关的症状。部分由于许多 与三环类抗抑郁药相关的不良副作用，更新更多 选择性化合物的开发和血清素（5-HT）的成功 选择性再摄取抑制剂（SSRIs）作为抗抑郁药的焦点转移 重新审视血清素在抑郁症中的作用。这是最 当今广泛使用的一类抗抑郁药。然而，还有一个不足 了解所有抗抑郁药如何发挥治疗作用。一个 继续努力了解抗抑郁药的作用机制 现在重点关注NE和5-HT的相互关系。拟议的研究 计划将尝试为之间的重要相互作用提供证据 这两种神经递质系统可能有助于解释 不同的药物发挥相似的临床益处。 具体来说，研究将检验这样一个假设：即使有选择性 神经元转运蛋白抑制剂在急性给药时可能会产生特异性作用， 他们将对其他系统采取间接行动 行政。这种在慢性病后改变多个单胺系统的能力 药物施用可能是治疗效果延迟的原因。 此外，还将比较一种非选择性再摄取抑制剂文拉法辛 与 NE 选择性抑制剂瑞波西汀和 5-HT 选择性再摄取 抑制剂氟西汀判断是否有非选择性的依据 单胺再摄取抑制可带来更大的治疗效果。在 此外，还将进行实验来检验以下假设： 5-HT 和 NE 系统介导对游泳压力源的行为反应。此外， 长期抗抑郁治疗对行为反应的影响和 将探讨与游泳应激源相关的神经化学效应。这 拟议研究的结果将提供对神经元适应的深入了解 涉及的两个单胺神经递质系统 抑郁症并可用于开发治疗抑郁症的药物 治疗抑郁症。