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

四氢孕酮和 γ-氨基丁酸受体 (GABA-A-R) 可塑性对有经前情绪症状的女性

• 批准号: 10363837
• 负责人: Liisa Victoria Hantsoo
• 金额: $ 25.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363837
• 关键词: Affect; Allopregnanolone; Animal Model; Anxiety; Blood; Brain Diseases; Characteristics; Chicago; Clinical; Clinical Trials; Communities; Complement; Control Groups; Data; Drops; Functional disorder; Future; GABA Agonists; GABA Receptor; Generalized Anxiety Disorder; Goals; Gold; Hormonal; Hormones; Human; Illinois; Impairment; Light; Literature; Luteal Phase; Mass Fragmentography; Measures; Menstrual cycle; Menstruation; Methodology; Methods; Mood Disorders; Morbidity - disease rate; National Institute of Mental Health; Outcome Measure; Panic Disorder; Participant; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma; Polymerase Chain Reaction; Population; Prevalence; Progesterone; Prospective Studies; Research; Research Personnel; Rodent; Rodent Model; Role; Scientist; Selective Serotonin Reuptake Inhibitor; Severities; Statistical Models; Steroids; Structure; Symptoms; System; Techniques; Testing; Time; Universities; Withdrawal; Woman; Work; antagonist; anxiety-like behavior; base; clinically significant; depressive symptoms; experience; external ear auricle; gamma-Aminobutyric Acid; mood symptom; neurosteroids; novel; novel marker; personalized medicine; phase change; pre-clinical; premenstrual dysphoric disorder; proliferative phase Menstrual cycle; prospective; receptor; recruit; reproductive; response; therapy development; treatment response

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.

项目总结