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

描述(申请人摘要)：以下修订后的竞争对手 应用程序反映PI的编程尝试，以检查 5-羟色胺能因子在差异发生机制中的作用 在抑郁症患者的抗抑郁反应(ADRs)中。这项提案已经 根据上一次审查进行了修订，并提出了直接扩展 奠定的基础，以及PI最初的调查结果 资金，表明两个血清素识别位点的差异， 5-羟色胺转运体(5-HTT)和5-HT1A受体都有助于 抗抑郁剂(AD)反应的差异。来自以下方面的初步发现 PI的实验室表明，表观亲和力的适当变化 5-HTT，以及随后5-HT1A的功能下调 受体，是去甲肾上腺素抗抑郁反应所必需的 发生。目前的提案将在两个重要方面扩展这些发现， 首先研究了它们的适用性扩展到使用 SSRI，并在治疗上利用这些新的原理来测试 新的药理策略，即是否阻断5-HT1A受体 会导致抗抑郁药物治疗的快速反应 在他们丧失资格的时间滞后之前对他们进行降级。这 Proposal还将采用新的策略来确定一些 抗抑郁药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和 5-HT1a受体在抑郁症患者中的作用，再次作为我们的 目前为止的数据。这个项目将探索来自我们实验室的新数据 与今年在5-HTT DNA中发现的两个新多态有关，其中一个在 SSCP鉴定的启动子区域，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，并扩展 这些技术旨在研究本项目中的5-HT1a受体。

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.