Allopregnanolone and Gamma-Aminobutyric Acid Receptor (GABA-A-R) Plasticity in Women with Premenstrual Mood Symptoms

项目摘要 大约有20%的女性经历了临床上显著的焦虑，易怒或抑郁症状， 月经周期的经前期（黄体期）。这包括经前焦虑症（PMDD）， 严重的情感障碍影响着全世界数百万的女性。尽管有这种发病率， 病理生理学落后于其他脑部疾病。PMDD病理生理学的一个潜在因素是 别孕烯醇酮（allopregnanolone，ALLO），一种孕酮代谢物和强效GABA-A受体（GABA-A-R）调节剂 在整个黄体期波动。重要的是，PMDD的啮齿动物模型表明受损的GABA-A-R 可塑性对ALLO波动的反应。基于这些临床前文献和来自 PI的K23（NIMH K23 MH 107831），拟议的研究将测试快速ALLO变化的假设， 在黄体期，与次优的GABA-A-R受体亚单位重构相互作用， 导致经前情绪症状。我们将评估67名月经周期正常的妇女（33 对照组，34例经前焦虑障碍（PMDD）），基于金标准每日记录， 问题的严重性。我们将获得两个结果指标：1）我们将测量血浆ALLO变化 在黄体期的多个时间点，使用精密气相色谱/质谱法 质谱（GC/MS）方法。2)我们将使用一种新的生物标志物，GABA-A-R亚基在外周血中的表达。 通过实时聚合酶链反应（RT-qPCR）测量血液单核细胞（PBMC），以检查 GABA-A-R亚单位在整个黄体期的表达。我们假设对照组和经前抑郁症患者 ALLO水平在黄体期下降将不同（例如，对照组将有更渐进的下降）， GABA-A-R亚基表达随着ALLO水平的下降而下降。结合这些强大的方法将使 我们研究了一个关于女性ALLO动力学和GABA-A-R可塑性的机制假说， 经前情绪症状，在一个前瞻性的受试者内的方式。调查人员带来了补充 专业知识; Hantsoo博士前瞻性研究PMDD女性，Pinna博士应用最先进的 方法研究ALLO对GABA-A-R功能的影响。这项研究是阐明 该人群中的ALLO-GABA-A-R动力学，并将导致检查ALLO-GABA-A-R的R 01 PMDD女性患者接受选择性5-羟色胺再摄取抑制剂（SSRIs）治疗时的动力学。 了解PMDD的病理生理学可能会为治疗开发提供信息;只有60%的PMDD女性 对一线治疗（SSRIs）有反应，正在开发新的GABA调节药物（例如， Brexanolone和sepranolone，GABA-A调节类固醇拮抗剂）。在完成有意义的工作之前， PMDD的治疗开发和个性化药物，机制如ALLO -GABA-A-R 必须澄清动态。

PROJECT SUMMARY Roughly 20% of women experience clinically significant anxiety, irritability, or depressive symptoms in the premenstrual (luteal) phase of the menstrual cycle. This includes premenstrual dysphoric disorder (PMDD), a severe affective disorder impacting millions of women worldwide. Despite this morbidity, research on PMDD’s pathophysiology lags behind that of other brain disorders. A potential contributor to PMDD’s pathophysiology is allopregnanolone (ALLO), a progesterone metabolite and powerful GABA-A receptor (GABA-A-R) modulator that fluctuates across the luteal phase. Importantly, rodent models of PMDD indicate impaired GABA-A-R plasticity in response to ALLO fluctuations. Building on this preclinical literature and clinical findings from the PI’s K23 (NIMH K23MH107831), the proposed research will test the hypothesis that rapid ALLO changes across the luteal phase, in interaction with suboptimal GABA-A-R receptor subunit reconfiguration, contribute to premenstrual mood symptoms. We will assess 67 women with regular menstrual cycles (33 controls, 34 with premenstrual dysphoric disorder (PMDD)) based on the gold standard Daily Record of Severity of Problems. We will capture two outcome measures: 1) We will measure plasma ALLO changes within subjects at multiple timepoints across the luteal phase using precise gas chromatography/mass spectrometry (GC/MS) methods. 2) We will use a novel biomarker, GABA-A-R subunit expression in peripheral blood mononuclear cell (PBMCs) measured via real-time polymerase chain reaction (RT-qPCR), to examine GABA-A-R subunit expression across the luteal phase. We hypothesize that controls and women with PMDD will differ in luteal phase decline in ALLO levels (e.g. controls will have a more gradual decline), and will differ in GABA-A-R subunit expression as ALLO levels decline. Combining these powerful methodologies will enable us to examine a mechanistic hypothesis about ALLO dynamics and GABA-A-R plasticity in women with premenstrual mood symptoms, in a prospective within-subject manner. The investigators bring complementary expertise; Dr. Hantsoo in prospectively studying women with PMDD, and Dr. Pinna in applying state-of-the-art methods to study the impact of ALLO on GABA-A-R function. This study represents a critical step in elucidating ALLO - GABA-A-R dynamics in this population, and will lead to an R01 that examines ALLO - GABA-A-R dynamics in women with PMDD when treated with selective serotonin reuptake inhibitors (SSRIs). Understanding PMDD’s pathophysiology may inform treatment development; only 60% of women with PMDD respond to the first-line treatment (SSRIs), and new GABA-modulating drugs are being developed (e.g. brexanolone and sepranolone, GABA-A modulating steroid antagonists). Before meaningful work is done in treatment development and personalized medicine in PMDD, mechanisms such as ALLO - GABA-A-R dynamics must be clarified.