5-HT1A RECEPTOR & 5-HTT--ROLE IN ANTIDEPRESSANT RESPONSE

描述（申请人摘要）：以下修订的竞争性 应用程序反映了PI的编程尝试，以检查 促肾上腺素能因子对差异机制的贡献 抑郁症患者的抗抑郁反应（ADR）。 该提案 根据上次审查结果进行了修订， 初步调查的结果为何， 资金，这表明，差异2血清素识别位点， 5-羟色胺转运体（5-HTT）和5-HT 1A受体都有助于 抗抑郁药（AD）反应的差异。 初步调查结果显示， PI的实验室表明，表观亲和力的适当变化 5-HTT的表达，以及随后5-HT 1A的功能下调， 受体，是抗抑郁反应所必需的去甲曲林， 发生. 本提案将在两个重要方面扩展这些发现， 首先审查其适用性的扩展， SSRI，并在治疗上利用这些新的原则来测试 新的药理学策略，即，阻断5-HT 1A受体 将通过功能性地产生快速的抗抑郁治疗反应， 在它们去磷酸化的时滞之前下调它们。 这 该提案还将采用新的战略来确定一些 抗抑郁反应差异的潜在机制 研究遗传差异是否可能导致不同的5-HTT， 5-HT 1A受体在抑郁症患者中的作用，再次作为我们的扩展， 迄今为止的数据。 这个项目将探索我们实验室的新数据 与今年在5-HTT DNA中发现的2种新的多态性有关，其中一种在 启动子区，以及一个新的RFLP，似乎， 在抑郁症患者的纯合子病例中更常见， 本课题将这些技术应用于5-HT 1A受体的研究。

DESCRIPTION (Applicant's Abstract): The following revised competitive application reflects the PI's programmatic attempt to examine the contribution of serotonergic factors to the mechanism underlying differences in antidepressant response (ADRs) in depressed patients. The proposal has been revised in response to the last review, and presents a direct extension of the groundwork laid, and the findings resulting from the PI's initial funding, suggesting that differences in 2 serotonin recognition sites, the serotonin transporter (5-HTT), and the 5-HT 1A receptor, both contribute to the variance in antidepressant (AD) responses. The initial findings from the PI's laboratory suggest that an adequate shift in the apparent affinity of the 5-HTT, and subsequent functional downregulation of the 5-HT 1A receptor, are necessary for an antidepressant response to nortripyline to occur. The present proposal will extend these findings in 2 important ways, first examining the extension of their applicability to treatment with an SSRI, and also to therapeutically exploit these novel principles to test a new pharmacologic strategy i.e., whether blockade of the 5-HT 1A receptors will result in a rapid antidepressant treatment response by functionally downregulating them prior to the time lag for their desentitzation. This proposal will also employ new strategies for determining some of the potential mechanisms underlying differences in antidepressant responses by examining whether genetic differences may contribute to different 5-HTT and 5-HT 1A receptor actions in depressed patients, again as an extension of our data to date. This project will explore new data from our laboratories related to 2 new polymorphisms found in the 5-HTT DNA this year, one in the promoter region identified by SSCP, as well as a new RFLP which appears to be more common in the homozygous case in depressed patients, and extend these techniques to study of the 5-HT 1A receptor in this project.