Targeting Anhedonia in Cocaine Use Disorder

 描述(由申请人提供)：开发有效的成瘾治疗方法一直很困难，部分原因可能是成瘾治疗研究一般针对药物使用的最终症状，并且有许多可能的药物使用的病因途径。该奖项的目标是在一个研究项目的背景下，支持玛格丽特·沃德尔博士的培训和职业发展，该项目将针对潜在的神经行为障碍，以改善成瘾治疗结果。沃德尔博士的长期职业目标是成为一名独立科学家，使用以神经科学为基础的方法开发成瘾治疗方法。拟议中的培训建立在沃德尔博士之前在健康成年人身上的药物效应方面的经验基础上，增加了她在以下方面的专业知识：1.临床研究，包括成瘾的行为和药物治疗；2.功能磁共振成像，直接测量潜在的神经过程；3.先进的贝叶斯统计方法，以增加从较小规模试验中获得的信息。这一培训将使沃德尔博士成为一名处于成瘾治疗开发前沿的独立科学家。补充性研究计划使用概念验证设计，针对一种特定的神经行为功能障碍-快感障碍，即对非药物奖励、可卡因使用障碍(CUD)，特别是应急管理(CM)缺乏兴趣或快乐，应急管理(CM)是一种有效的CUD治疗，在这种治疗中，个人因戒酒而获得非药物奖励。一些证据表明快感缺乏症对CM有负面影响，多巴胺(DAER)能药物可以改善CM的预后，这种改善可能是通过减少快感缺失来实现的。沃德尔博士自己的初步数据已经证实，快感缺乏预示着CUD的CM预后更差，而且DAR能药物可以增强对奖励的反应性。目前的拨款将整合和扩展这些发现，充分测试以下假设：快感缺乏是CUD中影响CM结局的关键神经行为功能障碍，DAR能药物通过减少快感缺乏来增强CM。这将通过以下方法完成：1.测试基础状态下快感缺乏症与CUD严重程度的关系，2.测试基线状态快感缺乏是否能预测4周强化CM治疗的结果。3.通过检测CM联合DAR能激动剂和单独使用DAR能刺激剂对CM的影响，以及对快感缺失和临床结果的影响，来检验快感缺失在CM的DAR增强中的作用。这项研究将使用一种基于神经科学的方法来治疗快感缺乏症，该方法测量主观、行为、心理生理和神经水平上可能存在的多个潜在的奖励功能缺陷。这项工作将：1.通过建立有效治疗的关键调节因素，为CUD的个性化药物做出贡献2.证明以神经行为过程为目标在成瘾治疗中的价值3.为Wardle博士提供临床研究、成像和贝叶斯统计学方面的培训，以应用这一方法加快成瘾治疗的发展。

 DESCRIPTION (provided by applicant): Development of effective addiction treatments has been difficult, likely in part because addiction treatment re- search has generally targeted the end symptom of drug use, and there are many possible etiological pathways to drug use. The goal of this award is to support the training and career development of Dr. Margaret Wardle, in the context of a research program that will instead target underlying neurobehavioral dysfunctions to improve addiction treatment outcomes. Dr. Wardle's long-term career goal is to become an independent scientist using a neuroscience-based approach to treatment development for addiction. The proposed training builds on Dr. Wardle's prior experience with drug effects in healthy adults by increasing her expertise in: 1. Clinical re- search, including behavioral and medication treatments for addiction; 2. Functional Magnetic Resonance Imaging to directly measure underlying neural processes; 3. Advanced Bayesian statistical methods to increase in- formation gained from smaller trials. This training will position Dr. Wardle as an independent scientist at the cutting edge of addiction treatment development. The complementary research program uses a proof-of- concept design, targeting one specific neurobehavioral dysfunction, anhedonia, i.e. lack of interest or pleasure in non-drug rewards, in Cocaine Use Disorder (CUD), and specifically in contingency management (CM), a validated CUD treatment in which individuals receive non-drug rewards for abstaining. Several lines of evidence suggest that anhedonia negatively affects CM, that dopaminergic (DAergic) drugs improve CM outcomes, and that this improvement may be mediated by reduced anhedonia. Dr. Wardle's own preliminary data has established that anhedonia predicts worse outcomes in CM for CUD, and that DAergic drugs can enhance responsiveness to rewards. The current grant will integrate and expand on these findings by fully testing the hypothesis that anhedonia is a key neurobehavioral dysfunction in CUD that affects CM outcomes, and that DAergic drugs enhance CM by reducing anhedonia. This will be accomplished by: 1. Testing the relationship of anhedonia to CUD severity at baseline, 2. Testing whether baseline anhedonia predicts outcomes in an intensive 4 week CM treatment. 3. Testing the role of anhedonia in DAergic enhancement of CM, by examining the effects of CM combined with a DAergic stimulant against CM alone and a DAergic stimulant alone, and measuring effects on anhedonia and clinical outcomes. This study will use a neuroscience-based approach to anhedonia that measures multiple possible underlying deficits in reward functioning across subjective, behavioral, psychophysiological and neural levels. This work will: 1. Contribute to personalized medicine for CUD by establishing a key moderator of a validated treatment 2. Demonstrate the value of targeting neurobehavioral processes in addiction treatment 3. Provide Dr. Wardle with training in clinical research, imaging, and Bayesian statistics needed to apply this approach to accelerate the development of addiction treatments.