Facilitation of Extinction Retention and Reconsolidation Blockade by IV Allopregnanolone in PTSD

IV 异孕酮在 PTSD 中促进消退保留和再巩固阻断

• 批准号: 10631103
• 负责人: ANN M. RASMUSSON
• 金额: $ 73.64万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631103
• 关键词: AMPA Receptors; Acute; Adrenergic beta-Antagonists; Allopregnanolone; Amygdaloid structure; Behavioral; Brain; Brain Stem; Cardiovascular system; Cyclic AMP-Dependent Protein Kinases; Dose; Environment; Episodic memory; Exposure to; Extinction; Fright; G-Protein-Coupled Receptors; Genetic; Hour; Human; Individual; Intravenous; Intravenous Bolus; Isomerism; Learning; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Modification; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurobiology; Neurons; Norepinephrine; Outcome; Participant; Pathway interactions; Patients; Phosphorylation; Physiological; Placebo Effect; Placebos; Plasma; Population; Post-Traumatic Stress Disorders; Prefrontal Cortex; Pregnanolone; Process; Production; Progesterone; Propranolol; Protein Kinase A Inhibitor; Protein Synthesis Inhibitors; Psychotherapy; Receptor Activation; Receptor Inhibition; Recovery; Refractory; Rest; Rodent; Serine; Short-Term Memory; Signal Transduction; Source; Stereoisomer; Stimulus; Sulfate; Sympathetic Nervous System; Synapses; Testing; Time; Training; Trauma; Woman; analog; conditioned fear; defense response; dehydroepiandrosterone; evidence base; fear memory; functional improvement; gamma-Aminobutyric Acid; high risk; hypothalamic-pituitary-adrenal axis; intravenous administration; learning extinction; male; member; memory consolidation; memory process; men; monoamine; neurosteroids; p38 Mitogen Activated Protein Kinase; prevent; receptor; receptor function; response; restraint; symptomatic improvement; treatment response

Trauma-focused psychotherapies show general efficacy in posttraumatic stress disorder (PTSD). However, symptom improvement in response to such treatments can vary substantially among individuals with PTSD. Several factors may contribute to treatment response including neurobiological factors that impact brain capacities needed to reprocess trauma memories and consolidate reconfigured brain circuits during recovery. During trauma-focused therapies, activation of a threat-related memory renders the memory “labile” and engages two competing processes: extinction and reconsolidation. Extinction involves: a) activation of prefrontal cortical (PFC) inhibition of amygdala-mediated physiological and behavioral defense responses, and acquisition and consolidation of new learning (e.g., the conditioned threat stimulus or CS+ no longer signals threat in the new time-space context). At the molecular level, extinction involves both synaptic long-term potentiation (LTP) and long-term depression (LTD). Extinction thus improves function, but is not permanent, as amygdala-mediated defense responses may reemerge in a new context, upon re-exposure to the original threat, or with the passage of time. PTSD has been associated with deficits in both extinction learning and retention. Reconsolidation blockade also may contribute to PTSD recovery. Protein synthesis inhibitors (not feasible in humans), beta-blockers, protein kinase A (PKA) inhibitors can block reconsolidation (if given within an hour of brief threat memory reactivation), the latter by disrupting phosphorylation of serine 845 residues on Glu-R1 AMPA receptors, thus limiting their synaptic incorporation—a prerequisite for memory reconsolidation. Thereafter, the former CS+-US association is “remembered”, but amygdala-mediated defense responses are not co-activated by the CS+. In the proposed study, we aim to use a standard 3-day differential fear- conditioning paradigm to demonstrate facilitation of extinction retention (Expt. 1) and reconsolidation blockade (Expt. 2) by appropriately timed intravenous (IV) administration of allopregnanolone (Allo). Allo is a metabolite of progesterone that positively modulates GABA effects at GABAA receptors; sulfated metabolites of Allo antagonize NMDA receptors. Men and women with PTSD are at high risk for Allo deficiency, and low resting Allo has been associated with poor extinction retention. In contrast, administration of an Allo analog after brief reactivation of conditioned fear in Allo-deficient rodents has been shown to block reconsolidation. In Expts. 1 and 2 of the study, 128 men and women with PTSD will undergo differential fear conditioning (Day 1). On Day 2 of Expt. 1, IV Allo vs. placebo will be infused after extinction training to raise plasma Allo to resting levels associated with optimum extinction retention; extinction retention will be tested on Day 3. On Day 2 of Expt. 2, high dose IV Allo vs. placebo will be administered immediately after fear memory reactivation by a singe CS+, and reconsolidation blockade will be tested on Day 3. If this study is successful, Allo could potentially be administered to augment trauma-focused therapy in treatment refractory PTSD patients.

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。然而，在这方面， 对这种治疗反应的症状改善在患有PTSD的个体中可以有很大的不同。 几个因素可能有助于治疗反应，包括影响大脑的神经生物学因素 在恢复过程中重新处理创伤记忆和巩固重新配置的大脑回路所需的能力。 在以创伤为中心的治疗期间，与威胁相关的记忆的激活使得记忆“不稳定”， 涉及两个相互竞争的过程：灭绝和重新整合。灭绝涉及：a）激活 前额叶皮层（PFC）抑制杏仁核介导的生理和行为防御反应， 获取和巩固新知识（例如，条件威胁刺激或CS+不再发出信号， 新时空背景下的威胁）。在分子水平上，灭绝既涉及突触的长期 增强（LTP）和长期抑制（LTD）。因此，灭绝可以改善功能，但不是永久性的，因为 杏仁核介导的防御反应可能会重新出现在一个新的背景下，当重新暴露于原来的 威胁，或者随着时间的推移。创伤后应激障碍与灭绝学习和 潴留再巩固阻断也可能有助于PTSD的恢复。蛋白质合成抑制剂（不 β受体阻滞剂、蛋白激酶A（PKA）抑制剂可以阻断再巩固（如果在 一小时的短暂威胁记忆再激活），后者通过破坏丝氨酸845残基的磷酸化， Glu-R1 AMPA受体，从而限制了它们的突触结合，这是记忆再巩固的先决条件。 此后，前CS+-US关联被“记住”，但杏仁核介导的防御反应被“记住”。 不被CS+共激活。在拟议的研究中，我们的目标是使用标准的3天差异恐惧- 条件反射范式，以证明促进灭绝保留（实验。1)和再巩固阻滞 （Expt. 2)通过适当定时静脉内（IV）施用别孕烯醇酮（Allo）。Allo是一种代谢物 孕酮，积极调节GABA对GABAA受体的作用; Allo的硫酸化代谢物 拮抗NMDA受体。患有PTSD的男性和女性患Allo缺乏症的风险很高， Allo与较差的灭绝保留有关。相比之下，在短暂给药后给予Allo类似物， 在同种异体缺陷的啮齿动物中条件性恐惧的再激活已经显示出阻断再巩固。摘录。1 在研究的第二天，128名患有PTSD的男性和女性将接受不同的恐惧条件反射（第一天）。天 2、实验1，在消退训练后，IV输注Allo与安慰剂，以将血浆Allo升高至静息水平 与最佳消光保留相关;将在第3天检测消光保留。实验第2天。2, 高剂量IV Allo对比安慰剂将在通过单一CS+恐惧记忆再激活后立即施用， 并在第3天检测再巩固阻滞。如果这项研究成功，Allo可能会成为 在难治性创伤后应激障碍患者中给予以增强创伤集中治疗。

项目成果

Pleiotropic endophenotypic and phenotype effects of GABAergic neurosteroid synthesis deficiency in posttraumatic stress disorder.

创伤后应激障碍中 GABA 能神经类固醇合成缺陷的多效性内表型和表型效应。

• DOI: 10.1016/j.coemr.2022.100359
• 发表时间: 2022
• 期刊: Current opinion in endocrine and metabolic research
• 作者: Rasmusson,AnnM;Novikov,Olga;Brown,KaylaD;Pinna,Graziano;Pineles,SuzanneL
• 通讯作者: Pineles,SuzanneL

A role for deficits in GABAergic neurosteroids and their metabolites with NMDA receptor antagonist activity in the pathophysiology of posttraumatic stress disorder.

• DOI: 10.1111/jne.13062
• 发表时间: 2022-03
• 期刊: JOURNAL OF NEUROENDOCRINOLOGY
• 影响因子: 3.2
• 作者: Rasmusson, Ann M.;Pineles, Suzanne L.;Brown, Kayla D.;Pinna, Graziano
• 通讯作者: Pinna, Graziano

Associations between PTSD-Related extinction retention deficits in women and plasma steroids that modulate brain GABAA and NMDA receptor activity.

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
• 发表时间: 2020
• 期刊: Neurobiology of stress
• 影响因子: 5
• 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
• 通讯作者: Rasmusson,AnnM