Synergy Between SSRIs and Ovarian Hormones

拟议研究的长期目标是为治疗绝经期患有潮热和情绪障碍的妇女提供新的方法。中脑和前脑区域（下丘脑、杏仁核）中5-羟色胺1A （5-HT1A）受体信号的脱敏可能是雌激素和选择性5-羟色胺再摄取抑制剂（SSRIs）（如氟西汀（百忧解））治疗绝经后妇女抑郁、焦虑和热潮红的潜在机制。然而，与SSRIs需要7-14天才能诱导治疗反应和5-HT1A受体脱敏不同，雌激素可以在给药后2天内产生5-HT1A受体脱敏。这种竞争性更新将研究雌激素治疗期间突触后下丘脑5-HT1A受体系统脱敏的机制。研究的重点是调节G蛋白信号- z1 (rgsz1)，一种作为Galphaz蛋白GTPase激活蛋白（Gz-GAP）的蛋白质，调节5-HT1A受体偶联的Galphaz蛋白与效应系统（如腺苷酸环化酶或钾通道）之间的相互作用。总体假设是雌激素诱导的5-HT1A受体信号的脱敏是由于rgsz1的表达增加。以下目标将检验这一假设。特异性Aim 1将验证雌激素受体β (ER β)介导RGSZ-1蛋白和mRNA表达增加以及5-HT1A受体脱敏的假设。特异性目的2将验证rgsz1上调介导下丘脑5-HT1A受体雌激素诱导脱敏的假设。特异性目标3将验证SSRIs（如氟西汀）与雌激素联合治疗导致两种互补机制的激活（分别减少Galphaz蛋白和增加rgsz1蛋白）的假设，从而导致5-HT1A受体信号的协同脱敏。这些建议的研究可能会为影响rgsz1调节的药物提供新的靶点，以治疗绝经期患有潮热和情绪障碍的妇女

The long term objectives of the proposed studies are to provide novel approaches towards treating women who suffer from hot flashes and mood disorders during menopause. Desensitization of serotonin 1A (5-HT1A) receptor signaling both in midbrain and forebrain regions (hypothalamus, amygdala) may be an underlying mechanism for the therapeutic effects of estrogen and of Selective Serotonin Reuptake Inhibitors (SSRIs), such as fluoxetine (Prozac (r) for depression, anxiety and hot flashes in post-menopausal women. However, unlike SSRIs, which require 7-14 days to induce a therapeutic response and a desensitization of 5-HT1A receptors, estrogen can produce a desensitization of 5-HT1A receptors within 2 days of administration. This competitive renewal will investigate the mechanisms responsible for the desensitization of post-synaptic hypothalamic 5-HT1A receptor systems during treatment with estrogen. The focus of the studies is on regulatory G protein signaling-Z1 (RGSZ-1), a protein that acts as a Galphaz protein GTPase Activating Protein (Gz-GAP) that regulates the interaction between 5-HT1A receptor-coupled Galphaz proteins and effector systems (such as adenylyl cyclase or potassium channels). The overall hypothesis is that estrogen-induced desensitization of 5-HT1A receptor signaling is due to increased expression of RGSZ-1. The following aims will test this hypothesis. Specific Aim 1 will test the hypothesis that estrogen receptor-beta (ER beta) mediates the increased expression of RGSZ-1 protein and mRNA and desensitization of the 5-HT1A receptors. Specific Aim 2 will test the hypothesis that up-regulation of RGSZ-1 mediates the estrogen-induced desensitization of hypothalamic 5-HT1A receptors. Specific Aim 3 will test the hypothesis that a treatment combining SSRIs (such as fluoxetine) with estrogen leads to activation of two complementary mechanisms (reduced Galphaz proteins and increased RGSZ-1 proteins, respectively), leading to a synergistic desensitization of 5-HT1A receptor signaling. The proposed studies may lead to novel targets for medications which affect the regulation of RGSZ-1 to treat women who suffer from hot flashes and mood disorders during menopause