Associations between PTSD-Related extinction retention deficits in women and plasma steroids that modulate brain GABAA and NMDA receptor activity.
Associations between PTSD-Related extinction retention deficits in women and plasma steroids that modulate brain GABAA and NMDA receptor activity.
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女性 PTSD 相关的消退保留缺陷与调节大脑 GABAA 和 NMDA 受体活性的血浆类固醇之间的关联。
DOI：
10.1016/j.ynstr.2020.100225
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发表时间：
2020
影响因子：
5
通讯作者：
Rasmusson,AnnM
中科院分区：
文献类型：
--
作者：
Pineles,SuzanneL;Nillni,YaelI;Pinna,Graziano;Webb,Andrea;ArditteHall,KimberlyA;Fonda,JenniferR;Irvine,John;King,MatthewW;Hauger,RichardL;Resick,PatriciaA;Orr,ScottP;Rasmusson,AnnM
多项研究表明，患有创伤后应激障碍（PTSD）的个体对消退学习的保留能力较差。大脑中的性腺激素信号传导似乎对患有和不患有创伤后应激障碍的女性对消退学习的保留产生不同的影响。与没有 PTSD 的创伤暴露女性相比，患有 PTSD 的女性在月经周期的黄体中期 (mLP) 期间（与卵泡早期 (eFP) 相比）表现出相对缺陷。与 PTSD 相关的黄体酮转化为其 GABA 能代谢物四氢孕酮 (Allo) 和孕酮 (PA) 的减少可能有助于这些发现。目前对患有 (n = 9) 和没有 (n = 9) PTSD 的创伤暴露女性的研究调查了消退保留与血浆 Allo + PA 水平之间的关联，以及 Allo + PA 与 5α-二氢孕酮 (5α-DHP)（Allo 的直接类固醇前体）的比率。该研究还调查了消退保留与 Allo + PA 与脱氢表雄酮 (DHEA)（一种肾上腺衍生的 GABAA 受体拮抗剂）的比率之间的关系。研究参与者在月经周期的 eFP 和 mLP 期间完成了差异恐惧调节。分析显示，患有（但并非没有）PTSD 的女性静息血浆 Allo + PA 水平与 MLP 期间的消退保留之间存在很强的正相关关系（例如，诊断 X Allo + PA 相互作用控制早期消退：β = −.0008，p=.003）。 Allo + PA 与 5α-DHP 的比例也出现了类似的模式 (β = -.165,p=.071)，与 PTSD 相关的 3α-羟基类固醇脱氢酶产生 Allo 和 PA 的阻断一致。 Allo + PA 与 DHEA 的比例似乎仅在 eFP 期间影响消退保留，此时 Allo + PA 和 DHEA 水平相当，因此可能会竞争对 GABAA 受体功能的影响。这项研究与雄性啮齿动物 PTSD 模型一致，将大脑 Allo 水平的实验性降低与消退保留缺陷联系起来，并表明针对 GABA 能神经类固醇合成中与 PTSD 相关的缺陷可能具有治疗作用。
Several studies have demonstrated poor retention of extinction learning among individuals with posttraumatic stress disorder (PTSD). Gonadal hormone signaling in brain appears to influence the retention of extinction learning differently in women with and without PTSD. Women with PTSD, compared to trauma-exposed women without PTSD, show relative deficits in extinction retention during the mid-luteal phase (mLP) of the menstrual cycle, compared to the early follicular phase (eFP). A PTSD-related reduction in conversion of progesterone to its GABAergic metabolites allopregnanolone (Allo) and pregnanolone (PA) may contribute to these findings. The current study in trauma-exposed women with (n = 9) and without (n = 9) PTSD investigated associations between extinction retention and plasma Allo + PA levels, as well as the ratio of Allo + PA to 5α-dihydroprogesterone (5α-DHP), the immediate steroid precursor for Allo. The study also investigated the relationship between extinction retention and the ratio of Allo + PA to dehydroepiandrosterone (DHEA), an adrenally-derived GABAAreceptor antagonist. Study participants completed differential fear-conditioning during both the eFP and mLP of the menstrual cycle. Analyses revealed a strong positive relationship between resting plasma Allo + PA levels and extinction retention during the mLP in the women with, but not without, PTSD (e.g., diagnosis X Allo + PA interaction controlling for early extinction: β = −.0008,p= .003). A similar pattern emerged for the Allo + PA to 5α-DHP ratio (β = -.165,p= .071), consistent with a PTSD-related block in production of Allo and PA at the enzyme 3α-hydroxysteroid dehydrogenase. The ratio of Allo + PA to DHEA appeared to influence extinction retention only during the eFP when Allo + PA and DHEA levels are comparable and thus may compete for effects on GABAAreceptor function. This study aligns with male rodent PTSD models linking experimental reductions in brain Allo levels to deficits in extinction retention and suggests that targeting PTSD-related deficits in GABAergic neurosteroid synthesis may be therapeutic.