GABAergic Neurotransmission in PTSD

PTSD 中的 GABA 能神经传递

• 批准号: 7297570
• 负责人: ANN M. RASMUSSON
• 金额: $ 13.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-13 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7297570
• 关键词: 20-alpha-Dihydroprogesterone; 3-Hydroxysteroid Dehydrogenases; 5-alpha-Dihydroprogesterone; Affect; Age; Allopregnanolone; Androgens; Androstenedione; Anesthetics; Anti-Anxiety Agents; Appendix; Applications Grants; Arousal; Brain; Butyric Acid; Butyric Acids; CYP11B1 gene; CYP17A1 gene; Cerebrospinal Fluid; Characteristics; Cholesterol; Chronic; Clinical; Communities; Condition; Contraceptive Usage; Cortodoxone; DNA; Data; Development; Enzymes; Epilepsy; Equilibrium; Estradiol; Exploratory/Developmental Grant; Factor Analysis; Female; Figs - dietary; Future; Gender; Gene Expression; General Population; Genetic; Glutamate Receptor; Goals; Hand; Hydrocortisone; Inorganic Sulfates; Investigation; Length; Link; Luteal Phase; Mass Fragmentography; Measurement; Measures; Mediating; Mental Depression; Mental disorders; Methods; Moods; Motor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neuraxis; Neurobiology; Neurons; Neurotransmitters; Numbers; Oral; Oxidoreductase; Patients; Pattern; Peripheral; Persons; Phase; Phenotype; Physiologic pulse; Plasma; Post-Traumatic Stress Disorders; Pregnanolone; Pregnenolone; Premenopause; Prevention; Progesterone; Progesterone Receptors; Property; Pulse taking; Purpose; Rate; Regulation; Reporting; Research; Research Proposals; Response Elements; Sample Size; Sampling; Severities; Stereoisomer; Steroid 11-beta-Monooxygenase; Steroids; Study Section; Study Subject; Symptoms; Techniques; Testosterone; Thinking; Time; Transcranial magnetic stimulation; Trauma; Traumatic Stress Disorders; Unspecified or Sulfate Ion Sulfates; Variant; Woman; age effect; base; brain pathway; clinical phenotype; dehydroepiandrosterone; depressive symptoms; design; disorder risk; experience; human study; improved; indexing; insight; interest; male; men; negative mood; neurotransmission; pregnane-20-one; proliferative phase Menstrual cycle; receptor; receptor expression; receptor function; response; sedative; sexual assault; sigma receptors

DESCRIPTION (provided by applicant): We recently measured cerebrospinal fluid (CSF) neuroactive steroids that modulate inhibitory gamma-amino- butyric acid (GABA)A and excitatory N-methyl-D-aspartate (NMDA) receptor function in premeno-pausal women with chronic PTSD using gas chromatography, mass spectrometry (GC-MS). Two of these steroids, 3a-hydroxy-5a-pregnan-20-one (allopregnanolone) and its equipotent stereoisomer, 3a-hydroxy-5b-pregnan- 20-one (pregnanolone), collectively termed ALLO, are the most potent and selective positive endogenous modulators of GABA action at brain GABAA receptors and demonstrate potent anxiolytic, sedative, anesthetic and neuroprotective effects. We also measured the precursors for ALLO: progesterone (PROG) and 5a- dihydroprogesterone (5a-DHP), as well as dehydroepiandrosterone (DHEA), a steroid that antagonizes and positively modulates, respectively, GABAA and NMDA receptor function. Levels of CSF PROG, 5a-DHP, and DHEA did not differ significantly between the PTSD and healthy subjects. PTSD ALLO levels were, however, low at just ~39% of healthy subject levels. In addition, the ALLO/DHEA ratio correlated strongly and negatively with depression and PTSD re-experiencing symptoms, suggesting that a reduction in inhibitory neurotransmission due to low ALLO levels influences the severity and comorbid features of PTSD. While intriguing, the small sample size, potential confounding effects of age and oral contraceptive use, and restriction of the sample to women with follicular phase PROG levels limit the generalizability of the findings. The purpose of this R21 proposal is thus to measure CSF levels of PROG, 5a-DHP, ALLO, and DHEA, as well as DHEAS, testosterone, cortisol and GABA in men with and without PTSD, and in women during the natural follicular and mid-luteal menstrual phases using a "within subjects" design. In the larger samples proposed, we can more reliably examine relationships between these steroids and patterns of PTSD and depressive symptoms. We also will examine whether transcranial magnetic stimulation (TMS) measures of cortical inhibition correlate with GABAergic neuroactive steroid and GABA measures. PTSD affects ~8% of the general population and 15-20% of persons exposed to sexual assault, compound community trauma, and combat; women are affected at twice the rate of men. The goal of this research is to identify new neurobiological targets to guide development of improved methods for PTSD treatment and prevention.

描述（由申请人提供）：我们最近使用气相色谱-质谱法（GC-MS）测量了患有慢性PTSD的绝经前暂停女性中调节抑制性γ-氨基丁酸（GABA）A和兴奋性N-甲基-D-天冬氨酸（NMDA）受体功能的脑脊液（CSF）神经活性类固醇。这些类固醇中的两种，3a-羟基-5a-胆甾烷-20-酮（别孕烯醇酮）及其等效立体异构体3a-羟基-5b-胆甾烷-20-酮（孕烯醇酮），统称为ALLO，是GABA作用于脑GABAA受体的最有效和选择性的正内源性调节剂，并表现出有效的抗焦虑、镇静、麻醉和神经保护作用。我们还测量了ALLO的前体：孕酮（PROG）和5 α-二氢孕酮（5 α-DHP），以及脱氢表雄酮（DHEA），一种分别拮抗和积极调节GABAA和NMDA受体功能的类固醇。CSF PROG、5a-DHP和DHEA的水平在PTSD和健康受试者之间没有显著差异。然而，PTSD ALLO水平仅为健康受试者水平的约39%。此外，ALLO/DHEA比率与抑郁症和PTSD再体验症状强烈负相关，表明由于低ALLO水平导致的抑制性神经传递减少影响PTSD的严重程度和共病特征。虽然有趣，但样本量小，年龄和口服避孕药使用的潜在混杂效应，以及样本仅限于卵泡期PROG水平的女性，限制了研究结果的普遍性。因此，本R21建议的目的是使用“受试者内”设计测量患有和不患有PTSD的男性以及女性在自然卵泡期和黄体中期月经期的PROG、5a-DHP、ALLO和DHEA以及DHEAS、睾酮、皮质醇和GABA的CSF水平。在提出的更大样本中，我们可以更可靠地检查这些类固醇与PTSD和抑郁症状模式之间的关系。我们还将研究经颅磁刺激（TMS）皮质抑制的措施是否与GABA能神经活性类固醇和GABA措施相关。PTSD影响约8%的普通人群和15-20%的暴露于性侵犯、复合社区创伤和战斗的人;女性的患病率是男性的两倍。这项研究的目的是确定新的神经生物学靶点，以指导开发PTSD治疗和预防的改进方法。