GABAergic Neurotransmission in PTSD

描述（由申请人提供）：我们最近使用气相色谱-质谱（GC-MS）测量了慢性创伤后应激障碍绝经前女性患者脑脊液（CSF）神经活性类固醇调节抑制性γ -氨基丁酸（GABA）A和兴奋性n -甲基- d -天冬氨酸（NMDA）受体功能。其中两种甾体，3a-羟基-5a-孕酮-20- 1（异孕酮）及其同效立体异构体3a-羟基-5b-孕酮-20- 1（孕酮），被称为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，具有有效的抗焦虑、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5a-二氢孕酮（5a- dhp），以及脱氢表雄酮（DHEA），一种分别拮抗和正调节GABAA和NMDA受体功能的类固醇。PTSD患者与健康受试者的CSF PROG、5a-DHP和DHEA水平无显著差异。然而，PTSD患者的ALLO水平较低，仅为健康受试者水平的39%。此外，ALLO/DHEA比值与抑郁和PTSD再经历症状呈显著负相关，提示低ALLO水平导致抑制性神经传递减少影响PTSD的严重程度和合并症特征。虽然有趣的是，小样本量，年龄和口服避孕药使用的潜在混淆效应，以及对卵泡期PROG水平妇女的样本限制限制了研究结果的普遍性。因此，R21提案的目的是使用“受试者内”设计，测量有和没有创伤后应激障碍的男性和女性在自然卵泡期和黄体中期月经期的脑脊液中PROG， 5a-DHP， ALLO和DHEA以及DHEAS，睾酮，皮质醇和GABA的水平。在更大的样本中，我们可以更可靠地检查这些类固醇与创伤后应激障碍和抑郁症状之间的关系。我们还将研究经颅磁刺激（TMS）的皮质抑制措施是否与GABA能神经活性类固醇和GABA措施相关。创伤后应激障碍影响约8%的普通人群和15-20%暴露于性侵犯、复合社区创伤和战斗的人；女性受影响的比例是男性的两倍。本研究的目的是确定新的神经生物学靶点，以指导PTSD治疗和预防的改进方法的发展。

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.