SYNERGY BETWEEN SSRIS AND OVARIAN HORMONES

SSRIS 和卵巢激素之间的协同作用

• 批准号: 2908242
• 负责人: LOUIS D VAN DE KAR
• 金额: $ 28.52万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-05 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2908242
• 关键词: autoradiography; biological signal transduction; combination chemotherapy; dissection; dorsal raphe nucleus; drug administration rate /duration; estrogen receptors; estrogens; female; fluoxetine; hormone regulation /control mechanism; hormone therapy; hypothalamus; in situ hybridization; injection /infusion; laboratory rat; neural transmission; nonhuman therapy evaluation; ovariectomy; progesterone; receptor sensitivity; serotonin inhibitor; serotonin receptor; women's health

Women suffer from disorders associated with serotonin (5-HT) deficiency, such as premenstrual syndrome (PMS) post-partum and post-menopausal depression, anxiety and bulimia. These mood and impulse control disorders are also associated with fluctuations in ovarian hormone levels. Estrogen can be used to treat some of these disorders, but serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac ) are the most effective drugs currently available. A major problem with SSRIs is the delay (2-3 weeks) in onset of clinical improvement of depression, a time which is associated with increased danger of suicide. Treatment with either fluoxetine or estrogen decreases the sensitivity of hypothalamic 5-HT1A receptor systems. These observations suggest that desensitization of 5-HT1A receptor signalling may underlie the therapeutic effectiveness of estrogen and SSRI treatments. Ovarian hormones act predominantly via genomic mechanisms, while fluoxetine induces adaptive responses via membrane proteins. Therefore, our central hypothesis is that estrogen will act synergistically with fluoxetine via complementary mechanisms to desensitize hypothalamic 5-HT1A receptor systems. Based on this hypothesis, we predict that estrogen or estrogen + progesterone will shorten the delay in the effects of SSRIs. The proposed studies will examine the mechanisms by which estrogen: 1) inhibits 5-HT1A signal transduction systems, and 2) reduces the delay in fluoxetine-induced desensitization of hypothalamic 5-HT1A receptor signalling. The proposed studies will use neuroendocrine, biochemical and molecular approaches to study the following specific aims: Specific Aim 1 will determine the doses of estrogen and progesterone that reduce hypothalamic 5-HT1A receptor function in ovariectomized rats. Specific Aim 2 will identify the estrogen receptor subtype(s) which mediate the effect of estrogen on 5-HT1A receptor systems in the hypothalamus. Specific Aim 3 will determine if estrogen shortens the delay in fluoxetine's effects on 5-HT1A receptor signalling. Specific Aim 4 will determine if progesterone increases estrogen's effectiveness in shortening the delay in fluoxetine-induced 5-HT1A receptor sub-sensitivity. The proposed studies will provide the scientific basis for the development of improved therapeutic regimens and novel drugs that provide faster clinical improvement in women suffering from PMS, depression, bulimia and anxiety disorders.

女性患有与血清素 (5-HT) 缺乏相关的疾病，例如经前综合症 (PMS)、产后和绝经后抑郁、焦虑和贪食症。 这些情绪和冲动控制障碍也与卵巢激素水平的波动有关。 雌激素可用于治疗其中一些疾病，但氟西汀（百忧解）等血清素再摄取抑制剂（SSRI）是目前最有效的药物。 SSRIs 的一个主要问题是抑郁症临床改善的延迟（2-3 周），而这一时间与自杀危险增加有关。 氟西汀或雌激素治疗会降低下丘脑 5-HT1A 受体系统的敏感性。 这些观察结果表明，5-HT1A 受体信号的脱敏可能是雌激素和 SSRI 治疗有效性的基础。卵巢激素主要通过基因组机制发挥作用，而氟西汀则通过膜蛋白诱导适应性反应。因此，我们的中心假设是雌激素将通过互补机制与氟西汀协同作用，使下丘脑 5-HT1A 受体系统脱敏。 基于这一假设，我们预测雌激素或雌激素+孕激素将缩短 SSRI 的作用延迟。 拟议的研究将探讨雌激素的机制：1）抑制 5-HT1A 信号转导系统，2）减少氟西汀诱导的下丘脑 5-HT1A 受体信号脱敏的延迟。 拟议的研究将使用神经内分泌、生化和分子方法来研究以下具体目标： 具体目标 1 将确定降低卵巢切除大鼠下丘脑 5-HT1A 受体功能的雌激素和孕激素剂量。 具体目标 2 将确定介导雌激素对下丘脑 5-HT1A 受体系统影响的雌激素受体亚型。 具体目标 3 将确定雌激素是否会缩短氟西汀对 5-HT1A 受体信号传导的影响的延迟。具体目标 4 将确定黄体酮是否会增加雌激素在缩短氟西汀诱导的 5-HT1A 受体亚敏感性延迟方面的有效性。 拟议的研究将为开发改进的治疗方案和新药物提供科学依据，从而为患有经前综合症、抑郁症、贪食症和焦虑症的女性提供更快的临床改善。