A role for deficits in GABAergic neurosteroids and their metabolites with NMDA receptor antagonist activity in the pathophysiology of posttraumatic stress disorder.
A role for deficits in GABAergic neurosteroids and their metabolites with NMDA receptor antagonist activity in the pathophysiology of posttraumatic stress disorder.
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DOI：
10.1111/jne.13062
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发表时间：
2022-03
影响因子：
3.2
通讯作者：
Pinna, Graziano
中科院分区：
文献类型：
--
作者：
Rasmusson, Ann M.;Pineles, Suzanne L.;Brown, Kayla D.;Pinna, Graziano
关键词：
以创伤为中心的心理治疗在创伤后应激障碍（PTSD）中显示出普遍的疗效，但结果在PTSD患者中差异很大，许多患者没有达到临床意义的症状改善。有几个因素可能导致治疗反应不佳，包括遗传或环境（例如，压力）对参与学习和记忆过程的神经生物学因素的影响，这些过程对PTSD的恢复至关重要。在这篇综述中，我们讨论了缺乏GABA能神经甾体代谢产物孕酮，allopregnanolone（Allo）和孕烯醇酮（PA）和PTSD症状的男性和女性或PTSD样行为异常的男性啮齿动物模型中观察到的PTSD之间的关系。我们还回顾了与PTSD恢复相关的学习和记忆过程的作用和分子基础，包括消退、消退保留、重新激活的厌恶记忆的重新巩固和情景非厌恶记忆。然后，我们讨论了临床前和临床研究，支持在这些学习和记忆过程中的GABA能神经类固醇和硫酸化代谢产物的Allo和PA，变构拮抗N-甲基-D-天冬氨酸（NMDA）受体功能的作用。研究支持可能的治疗影响，适当的时间，急性管理的Allo或Allo类似物，以促进灭绝保留和/或块重新巩固厌恶的记忆也进行了审查。最后，我们讨论了未来在这一领域的研究方向。检查孕酮的几种代谢物以及大脑和外周产生的其他母体类固醇的神经活性衍生物在PTSD中的各种复合作用可能会扩大治疗开发的目标。确定这些神经活性类固醇对常见的PTSD共病精神和医学疾病的贡献，以及亚群特定的潜在功能失调的生理过程，如下丘脑-垂体-肾上腺轴和免疫系统失调，也可能使开发更有效的多系统精确药物，以预防和治疗极端和慢性应激的更广泛的多形后遗症。
Trauma-focused psychotherapies show general efficacy in posttraumatic stress disorder (PTSD), but outcomes vary substantially among individuals with PTSD and many patients do not achieve clinically meaningful symptom improvement. Several factors may contribute to poor treatment response, including genetic or environmental (e.g., stress) effects on neurobiological factors involved in learning and memory processes critical to PTSD recovery. In this review, we discuss the relationship between deficient GABAergic neurosteroid metabolites of progesterone, allopregnanolone (Allo) and pregnanolone (PA) and PTSD symptoms in men and women or PTSD-like behavioral abnormalities observed in male rodent models of PTSD. We also review the role and molecular underpinnings of learning and memory processes relevant to PTSD recovery, including extinction, extinction retention, reconsolidation of reactivated aversive memories, and episodic non-aversive memory. We then discuss preclinical and clinical research that supports a role in these learning and memory processes for GABAergic neurosteroids and sulfated metabolites of Allo and PA that allosterically antagonize N-methyl-D-aspartate (NMDA) receptor function. Studies supporting the possible therapeutic impact of appropriately timed, acutely administered Allo or Allo analogues to facilitate extinction retention and/or block reconsolidation of aversive memories are also reviewed. Finally, we discuss important future directions for research in this area. Examining the varied and composite effects in PTSD of the several metabolites of progesterone, as well as neuroactive derivatives of other parent steroids produced in the brain and the periphery will likely enable a broadening of targets for treatment development. Defining the contributions of these neuroactive steroids to common PTSD-comorbid psychiatric and medical conditions, as well as subpopulation-specific underlying dysfunctional physiological processes such as hypothalamic-pituitary-adrenal axis and immune system dysregulation, may also enable development of more effective multi-system precision medicines to prevent and treat the broader, polymorbid sequelae of extreme and chronic stress.
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影响因子：
4.8
作者：
Drury, Jason E.;Di Costanzo, Luigi;Christianson, David W.
通讯作者：
Christianson, David W.
影响因子：
4.1
作者：
Barbaccia, ML;Roscetti, G;Biggio, G
通讯作者：
Biggio, G
影响因子：
17.7
作者：
Brunet, Alain;Saumier, Daniel;Pitman, Roger K.
通讯作者：
Pitman, Roger K.
影响因子：
2.3
作者：
Chin, Vivien S.;Van Skike, Candice E.;Matthews, Douglas B.
通讯作者：
Matthews, Douglas B.
DOI：
10.1080/13803390490919335
发表时间：
2005-10-01
影响因子：
2.2
作者：
Davidson, PSR;Cook, SP;Rapcsak, SZ
通讯作者：
Rapcsak, SZ