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

基本信息

批准号：
10426067
负责人：
ANN M. RASMUSSON
金额：
$ 74.75万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
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/10426067
关键词：
AMPA Receptors Acute Adrenergic beta-Antagonists Allopregnanolone Amygdaloid structure Behavioral Brain Brain Stem Cardiovascular system Cyclic AMP-Dependent Protein Kinases Dose Episodic memory Exposure to Extinction (Psychology)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 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 gamma-Aminobutyric Acid high risk hypothalamic-pituitary-adrenal axis improved functioning learning extinction male memory consolidation memory process men monoamine neurosteroids prevent receptor receptor function response symptomatic improvement treatment response

项目摘要

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.

以创伤为重点的心理治疗表现出创伤后应激障碍（PTSD）的普遍效率。然而，在PTSD患者中，症状改善症状可能会有很大差异。几个因素可能导致治疗反应，包括影响大脑的神经生物学因素重新处理创伤记忆所需的能力并在恢复过程中巩固了重新配置的大脑回路。在以创伤为重点的疗法中，激活与威胁相关的记忆使记忆“不稳定”和参与两个竞争过程：扩展和重新整合。灭绝涉及：a）激活前额叶皮质（PFC）抑制杏仁核介导的生理和行为防御反应，以及新学习的获取和巩固（例如条件威胁刺激或CS+不再信号在新的时空上下文中的威胁）。在分子水平上，扩展涉及长期突触增强（LTP）和长期抑郁症（LTD）。因此，灭绝改善了功能，但不是永久的，因为杏仁核介导的防御反应可能会在重新暴露于原始威胁或随着时间的流逝。 PTSD与扩展学习和保留。重新固定封锁也可能导致PTSD恢复。蛋白质合成抑制剂（不是在人类中可行），β受体阻滞剂，蛋白激酶A（PKA）抑制剂可以阻止重新溶解（如果在内给出一个小时的短暂威胁记忆重新激活），后者通过破坏丝氨酸845的磷酸化遭受 GLU-R1 AMPA受体，因此限制了它们的突触保险，这是重新整合记忆的先决条件。此后，前CS+-US协会被“记住”，但杏仁核介导的防御反应是 CS+未共激活。在拟议的研究中，我们的目标是使用标准的3天差异恐惧 - 调节范式以演示扩展保留的设施（Expt。1）和重新固定封锁（ext。2）通过适当定时的静脉内（IV）给药异源（Allo）。阿罗是一种代谢物孕激素对GABAA受体的GABA效应进行积极调节；阿罗的硫酸盐代谢物拮抗NMDA受体。患有PTSD的男性和女性患Allo缺乏症的风险很高，休息较低 Allo与延长率差有关。相反，简短后给予Allo类似物已经证明，有条件恐惧的调节性恐惧的重新活化已被证明可以阻止重新溶解。在分机中。 1 和2项研究，有128名具有PTSD的男性和女性将经历差异恐惧调节（第1天）。在一天 expt 2。 1，IV Allo vs.安慰剂将在延长训练后注入以将血浆allo提高到静止水平与最佳扩展保留相关；扩展保留率将在第3天进行测试。在Ext的第2天。 2，，高剂量IV Allo vs.安慰剂将在恐惧记忆重新激活后立即管理并将在第3天进行重新固定封锁。如果这项研究成功，Allo可能会可能是为了增加治疗难治性PTSD患者的以创伤为中心的治疗。