Fyn Kinase Inhibitors and Alcohol Drinking Behaviors in Heavy Drinkers

项目3：Fyn激酶抑制剂与重度饮酒者的饮酒行为 Suchitra Krishnan-Sarin博士 摘要 从历史上看，包括酒精在内的物质使用障碍的成功治疗方法的发展 饮酒，一直是基于对神经化学机制的理解， 条件CTNA 4具有理解细胞内转录因子的作用的新的和翻译的焦点。 与蛋白酪氨酸磷酸酶相关的信号转导机制，在介导酒精诱导的 多巴胺和谷氨酸信号的干扰，以及这些相互作用与酒精的相关性 奖励和饮酒以及酗酒习惯。这个项目，P3，是一个重要的组成部分， 翻译CTNA 4，将评估Fyn激酶抑制剂Saractinib是否改变饮酒行为， 酗酒者Saractinib是由Astra Zeneca开发的Fyn激酶抑制剂， NMDA受体信号传导，并已用于多项研究与健康对照，患者 实体瘤和阿尔茨海默病患者。P3在两个方面都具有内在的创新性， 概念和应用，因为它确定了临床知识的重要差距-如何 靶向NMDA受体功能，以减少饮酒，而不增加积极的酒精效应-和 然后进行了一项实验，将一种新的治疗药物和一种行为药物结合起来， 科学工具，酒精饮用范式（ADP）来调查这个问题。该项目 核心服务，但也支持CTNA核心的目标，包括临床和 翻译核心，提出独特的问题，如“习惯”和新的神经成像的作用， 预测药物反应的标志物。P3将解决Fyn是否 用Saractinib抑制激酶，改变酗酒者的饮酒和渴望， ADP它还将评估Saracatinib是否会改变酒精的作用，如刺激和镇静， 检查治疗反应的各种新的预测因素，包括习惯，冲动，缺陷 在学习中对奖励/惩罚的反应和功能性大脑的神经成像标记物 连通性。

Project 3: Fyn Kinase Inhibitors and Alcohol Drinking Behaviors in Heavy Drinkers Suchitra Krishnan-Sarin, Ph.D. Abstract Historically, development of successful treatments for substance use disorders, including alcohol drinking, has been based on an understanding of the neurochemical mechanisms mediating the condition. CTNA4 has a novel and translational focus on understanding the role of an intracellular signaling mechanism, related to protein tyrosine phosphatases, in mediating alcohol induced disturbances in DA and glutamate signaling, and the relevance of these interactions to alcohol reward and drinking and alcohol habits. This project, P3, which is an important component of the translational CTNA4, will evaluate if a Fyn Kinase inhibitor, Saractinib, alters drinking behavior in heavy drinkers. Saractinib is a Fyn Kinase inhibitior developed by Astra Zeneca that will target NMDA receptor signaling and has been used in multiple studies with healthy control, patients with solid tumors and patients with Alzheimers disease. P3 is inherently innovative in both its conception and application because it identifies an important gap in clinical knowledge –how to target NMDA receptor function to reduce drinking without increasing positive alcohol effects- and then brings to bear an experiment which combines a novel therapeutic agent and a behavioral science tool, the Alcohol drinking paradigm (ADP) to investigate this question. The project is served by the cores but also supports the goals of the CTNA cores, including the clinical and translational cores, to ask unique questions like the role of “habit” and novel neuroimaging markers in predicting medication response. P3 will address the primary questions of whether Fyn kinase inhibition with Saractinib, alters alcohol drinking and craving in heavy drinkers using the ADP. It will also evaluate if Saracatinib alters alcohol effects like stimulation and sedation and examine various novel predictors of treatment response including habit, impulsivity, deficiencies in learning in response to rewards/punishment and neuroimaging markers of functional brain connectivity.