Dopamine Enhancement of fear extinction learning in PTSD

描述（由申请人提供）：响应RFA-MH-15-300的R21/R33申请旨在证明创伤后应激障碍新型联合治疗的靶点参与和临床可行性。创伤后应激障碍与生活质量差有关，并与身体和精神疾病并存。虽然基于创伤后应激障碍的心理治疗已被证明是有效的，但高达40%的人在治疗后保留了PTSD诊断。因此，提高治疗效果的新方案可能会对公共卫生产生重大影响。最近的基础研究表明，恐惧消退学习记忆的巩固至少部分是多巴胺介导的，并且在巩固窗口中增强多巴胺信号可以减少随后暴露于恐惧线索时的恐惧反应。拟议项目的总体目标是证明在学习后巩固窗口中促进多巴胺信号传导的可行性，作为一种新的手段，提高与攻击性暴力（身体或性侵犯）相关的创伤后应激障碍成年女性的治疗效果。在R21靶点参与阶段，我们将测试多巴胺神经传递的内源性和外源性操纵对1）多巴胺能静息态网络的急性功能组织的影响，以及2）通用（即，实验室诱导的）恐惧消退学习，同时使用神经影像学，心理生理学，和自我报告评估的妇女与创伤后应激障碍（目标1）。在R33临床阶段，我们试图复制和扩展目标参与的恐惧消退学习的临床背景下，表意创伤记忆和情绪反应的创伤线索与创伤后应激障碍的妇女使用并发神经影像学，心理生理学和自我报告的评估（目标2）。目标参与（目标1）和创伤记忆和对创伤线索的情绪反应（目标2）的临床目标的有效性的成功证明，将提供关键的科学支持的可行性相结合的治疗为基础的治疗与药理学药物，促进多巴胺信号作为一种手段，以改善治疗结果的创伤后应激障碍。

DESCRIPTION (provided by applicant): This R21/R33 application in response to RFA-MH-15-300 seeks to demonstrate target engagement and clinical viability for a novel combination therapy for Posttraumatic Stress Disorder. PTSD is associated with poor quality of life and comorbidity with both physical and mental illness. While exposure-based psychological treatments have proven efficacious, up to 40% retain PTSD diagnoses following treatment. Thus, new protocols to boost treatment efficacy can have a significant public health impact. Recent basic research suggests that consolidation of fear extinction learning memories is at least partly dopamine-mediated and that boosting dopamine signaling in the consolidation window can decrease fear responding during subsequent exposure to fear cues. The overall goal of the proposed project is to demonstrate the viability of boosting dopamine signaling in the post-learning consolidation window as a novel means of boosting therapy outcomes among adult women with PTSD related to assaultive violence (physical or sexual assault). In the R21 target engagement phase, we will test the impact of endogenous and exogenous manipulations of dopamine neurotransmission on 1) acute functional organization of dopaminergic resting-state networks, and 2) the consolidation of generic (i.e., laboratory-induced) fear extinction learning using concurrent neuroimaging, psychophysiological, and self-report assessments among women with PTSD (Aim 1). In the R33 clinical phase, we seek to replicate and extend target engagement to the clinical context of fear extinction learning for ideographic trauma memories and emotional responding to trauma cues among women with PTSD using concurrent neuroimaging, psychophysiological, and self-report assessments (Aim 2). Successful demonstration of target engagement (Aim 1) and efficacy for the clinical target of trauma memories and emotional responding to trauma cues (Aim 2) would provide critical scientific support of the viability of combining exposure-based therapy with pharmacological agents that boost dopamine signaling as a means to improve treatment outcomes for PTSD.