Synergy Between SSRIs and Ovarian Hormones

拟议研究的长期目标是为治疗更年期潮热和情绪障碍的女性提供新的方法。中脑和前脑区域(下丘脑、杏仁核)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(SSRI)治疗绝经后女性抑郁、焦虑和潮热的潜在机制。然而，与SSRI不同的是，SSRI需要7-14天才能诱导5-HT1A受体的治疗反应和脱敏，而雌激素可以在给药后2天内使5-HT1A受体脱敏。这一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。研究的重点是调节性G蛋白信号转导-Z1(RGSZ-1)，它作为Galphaz蛋白GTP酶激活蛋白(Gz-GAP)，调节5-HT1a受体偶联的Galphaz蛋白与效应系统(如腺苷环化酶或钾通道)之间的相互作用。总的假设是雌激素诱导的5-HT1a受体信号的脱敏是由于RGSZ-1的表达增加。以下目标将检验这一假设。特定目的1将验证雌激素受体-β(ERβ)介导RGSZ-1蛋白和mRNA表达增加以及5-HT1a受体脱敏的假设。特定目的2将验证RGSZ-1上调介导雌激素诱导的下丘脑5-HT1A受体脱敏的假设。具体目标3将检验这样一种假设，即SSRIs(如氟西汀)与雌激素联合治疗会激活两种互补机制(分别是Galphaz蛋白减少和RGSZ-1蛋白增加)，从而导致5-HT1A受体信号的协同脱敏。拟议的研究可能导致影响RGSZ-1调节的药物治疗更年期潮热和情绪障碍的新靶点

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