GABAergic Neurotransmission in PTSD

PTSD 中的 GABA 能神经传递

• 批准号: 7496147
• 负责人: ANN M. RASMUSSON
• 金额: $ 23.92万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496147
• 关键词: 20-alpha-Dihydroprogesterone; 5-alpha-Dihydroprogesterone; Affect; Age; Allopregnanolone; Androgens; Androstenedione; Anesthetics; Anti-Anxiety Agents; Appendix; Applications Grants; Arousal; Brain; Butyric Acid; Butyric Acids; 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; Hydroxysteroid Dehydrogenases; 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; 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）：我们最近测量了脑脊液（CSF）神经活性类固醇，这些类固醇调节抑制性γ-氨基酸 - 丁酸（GABA）A和兴奋性N-甲基-D-Appartate（NMDA）在使用慢性PTSD的慢性PTSD中的妇女的兴奋性N-甲基-D-天冬氨酸（NMDA）受体功能。 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,镇静剂，麻醉和神经保护作用。我们还测量了Allo的前体：孕酮（Prog）和5a-二氢丙酮（5A-DHP），以及脱氢双凝蛋白（DHEA），一种类固醇，一种分别拮抗和阳性调节的类固醇，GABAA和NMDA受体功能。 PTSD和健康受试者之间的CSF POG，5A-DHP和DHEA的水平没有显着差异。但是，PTSD Allo水平较低，仅在健康受试者水平的〜39％。此外，Allo/DHEA比与抑郁症和PTSD重新体验症状密切相关，这表明由于较低的Allo水平而导致的抑制性神经传递降低会影响PTSD的严重性和合并特征。在吸引人的同时，样本量较小，年龄和口服避孕药的潜在混杂作用以及对卵泡相位prog含量水平的妇女的限制限制了发现的普遍性。因此，该R21提案的目的是测量在有和没有PTSD的男性中，在具有和没有PTSD的男性中，在具有和没有PTSD的男性中，在具有和没有PTSD的女性中，在自然卵泡和中性卵泡中，使用“受试者”中的妇女中的女性以及女性中的女性中的男性和女性中的女性中的DHEAS，睾丸激素，皮质醇和GABA的目的是测量脑脊液水平。在提出的较大样品中，我们可以更可靠地检查这些类固醇与PTSD模式与抑郁症状之间的关系。我们还将检查皮质抑制的经颅磁刺激（TMS）是否与GABA能神经活性类固醇和GABA测量相关。 PTSD影响了约8％的普通人群，15-20％的人受到性侵犯，复合社区创伤和战斗的影响；妇女的影响是男性的两倍。这项研究的目的是确定新的神经生物学靶标，以指导改进的PTSD治疗和预防方法的开发。

项目成果

Composite contributions of cerebrospinal fluid GABAergic neurosteroids, neuropeptide Y and interleukin-6 to PTSD symptom severity in men with PTSD.

脑脊液 GABA 能神经类固醇、神经肽 Y 和白细胞介素 6 对 PTSD 男性 PTSD 症状严重程度的综合影响。

• DOI: 10.1016/j.ynstr.2020.100220
• 发表时间: 2020
• 期刊: Neurobiology of stress
• 影响因子: 5
• 作者: Kim,ByungKil;Fonda,JenniferR;Hauger,RichardL;Pinna,Graziano;Anderson,GeorgeM;Valovski,IvanT;Rasmusson,AnnM
• 通讯作者: Rasmusson,AnnM

Overview of the Molecular Steps in Steroidogenesis of the GABAergic Neurosteroids Allopregnanolone and Pregnanolone.

• DOI: 10.1177/2470547018818555
• 发表时间: 2018-01-01
• 期刊: Chronic stress (Thousand Oaks, Calif.)
• 作者: Liang, Jennifer J;Rasmusson, Ann M
• 通讯作者: Rasmusson, Ann M