Dopamine enhancement of fear extinction learning in PTSD

描述（由申请人提供）：本R21/R33申请响应RFA-MH-15-300，旨在证明创伤后应激障碍新型联合疗法的靶向性和临床可行性。创伤后应激障碍与生活质量差以及身体和精神疾病的共病有关。虽然基于暴露的心理治疗已被证明是有效的，但高达40%的患者在治疗后仍被诊断为创伤后应激障碍。因此，提高治疗效果的新方案可以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，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。该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，作为一种提高与攻击性暴力（身体或性侵犯）相关的成年女性创伤后应激障碍治疗效果的新方法。在R21目标参与阶段，我们将测试多巴胺神经传递的内源性和外源性操作对以下方面的影响：1)多巴胺能静息状态网络的急性功能组织；2)PTSD女性患者中通用（即实验室诱导的）恐惧消退学习的巩固（即，使用同步神经成像、心理生理和自我报告评估）（目的1）。在R33临床阶段，我们试图通过神经成像、心理生理和自我报告评估来复制和扩展目标参与到PTSD女性患者的恐惧消退学习的临床背景中，以学习表意创伤记忆和对创伤线索的情绪反应。目标参与（目标1）和创伤记忆和创伤线索情绪反应临床目标（目标2）的有效性的成功论证，将为暴露治疗与促进多巴胺信号的药物结合作为改善创伤后应激障碍治疗结果的手段的可行性提供关键的科学支持。

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.