Dopamine Enhancement of fear extinction learning in PTSD

描述(由申请人提供)：这份R21/R33申请是对RFA-MH-15-300的回应，旨在证明一种治疗创伤后应激障碍的新型联合疗法的目标参与度和临床可行性。创伤后应激障碍与较差的生活质量以及与身体和精神疾病的共病有关。虽然基于暴露的心理治疗被证明是有效的，但高达40%的人在治疗后保留了创伤后应激障碍的诊断。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由多巴胺介导的，加强巩固窗口中的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增强多巴胺信号的可行性，作为一种新的手段，提高患有与攻击性暴力(身体或性侵犯)有关的创伤后应激障碍的成年女性的治疗结果。在R21目标参与阶段，我们将测试内源性和外源性操作多巴胺神经传递对1)多巴胺能静息状态网络的急性功能组织的影响，以及2)使用同时进行的神经成像、心理生理学和自我报告评估巩固患有创伤后应激障碍的女性的一般(即，实验室诱导的)恐惧消退学习(目标1)。在R33临床阶段，我们试图通过同时进行神经成像、心理生理学和自我报告评估，将目标参与复制和扩展到临床背景下，即表意创伤记忆的恐惧消退学习和对创伤线索的情感反应(目标2)。成功展示创伤记忆和对创伤提示的情感反应的临床靶点的目标参与(目标1)和有效性(目标2)将为将基于暴露的治疗与促进多巴胺信号转导的药物相结合的可行性提供关键的科学支持，以此作为改善创伤后应激障碍治疗结果的手段。

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.