SYNERGY BETWEEN SSRIS AND OVARIAN HORMONES

女性患有与血清素（5-HT）缺乏相关的疾病，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，但血清素再摄取抑制剂（SSRIs），如氟西汀（百忧解）是目前可用的最有效的药物。SSRIs的一个主要问题是延迟（2-3周）抑郁症临床改善的开始，这一时间与自杀的危险增加有关。氟西汀或雌激素治疗可降低下丘脑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治疗效果的基础。卵巢激素主要通过基因组机制起作用，而氟西汀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+孕激素会缩短SSRIs作用的延迟。拟制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。拟开展的研究将采用神经内分泌、生化和分子方法研究以下具体目的：具体目的1将确定雌激素和孕激素的剂量对去卵巢大鼠下丘脑5-HT1A受体功能的影响。特异性目的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。特异性目的3将确定雌激素是否缩短氟西汀对5-HT1A受体信号传导作用的延迟。特异性目的4将确定黄体酮是否增加雌激素在缩短氟西汀诱导的5-HT1A受体亚敏感延迟的有效性。拟议的研究将为改进治疗方案和新药的开发提供科学基础，这些方案和新药可以更快地改善患有经前症候群、抑郁症、贪食症和焦虑症的妇女的临床状况。

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.