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

项目总结 大约20%的女性在临床上经历了显著的焦虑、易怒或抑郁症状 月经周期的月经前(黄体)阶段。这包括经前焦虑症(PMDD)， 严重的情感障碍影响着全球数百万女性。尽管有这种发病率，但对经前抑郁症的研究 病理生理学落后于其他脑部疾病。PMDD的病理生理学的一个潜在因素是 孕酮代谢产物和强大的GABA-A受体(GABA-A-R)调节剂别孕酮(Allo) 在整个黄体期都有波动。重要的是，PMDD的啮齿动物模型表明GABA-A-R受损 响应ALLO波动的可塑性。基于这一临床前文献和临床研究结果 Pi的K23(NIMH K23MH107831)，拟议的研究将检验等位基因快速变化的假设 在整个黄体期，在次优的GABA-A-R受体亚基重组的作用下， 会导致经前情绪症状。我们将评估67名有规律月经周期的女性(33名 对照，34例患有经前焦虑症(PMDD)) 问题的严重性。我们将捕获两个结果指标：1)我们将测量血浆Allo的变化 在黄体期多个时间点的受试者内使用精确的气相色谱/质谱仪 光谱分析(GC/MS)方法。2)我们将使用一种新的生物标志物，GABA-A-R亚基在外周组织中的表达 通过实时定量聚合酶链式反应(RT-qPCR)检测外周血单个核细胞(PBMC)，以检测 GABA-A-R亚基在黄体期的表达。我们假设控制组和患有PMDD的女性 ALLO水平在黄体期的下降将有所不同(例如，对照组将有更渐进的下降)，并且将有所不同 在GABA-A-R亚基中的表达随着等位基因水平的下降而下降。将这些强大的方法结合在一起将使 美国将检验有关等位基因动力学和GABA-A-R可塑性的机制假说 经前情绪症状，以预期的受试者内的方式。调查人员带来了补充 专业知识；Hantsoo博士前瞻性研究患有PMDD的女性，Pinna博士应用最先进的技术 方法研究Allo对GABA-A-R功能的影响。这项研究代表了阐明 该群体中的Allo-GABA-A-R动态，并将导致检测Allo-GABA-A-R的R01 选择性5-羟色胺再摄取抑制剂(SSRIs)治疗PMDD的女性患者的动力学。 了解PMDD的病理生理学可能有助于治疗的发展；只有60%的PMDD妇女 对一线治疗(SSRIs)有反应，正在开发新的GABA调节药物(例如， 布雷沙诺酮和塞普诺酮，GABA-A调节类固醇拮抗剂)。在完成有意义的工作之前 PMDD的治疗进展和个体化药物，Allo-GABA-A-R等机制 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.