Translational Addiction Sciences Center

描述(申请人提供)：可卡因的滥用和依赖继续在美国和世界范围内造成相当大的个人、健康和社会损失。这种疾病的循环进行性阻碍了保持禁欲的努力，复发往往是沉淀的。 在面对与可卡因相关的线索(线索反应性)时的冲动行为和渴望。5-羟色胺(5-羟色胺)神经传递是机械连接这些表型的战略联系。翻译成瘾科学中心(TASC)由一个从分子到细胞再到动物再到人类的翻译团队组成，其长期研究目标是明确揭示5-羟色胺在成瘾神经生物学中的作用，并将这一知识整合到成瘾的主要理论结构中。TASC的中心研究主题是，冲动行为和线索反应与5-HT2A受体(5-HT2AR)和5-HT2CR定位于额叶-纹状体-丘脑前部回路的5-羟色胺信号中断有机械联系。我们的前提是恢复5-HT2AR：5-HT2CR平衡将修复皮质纹状体缺陷并改善复发。TASC由一支经验丰富的翻译团队领导，他们融合了经典和最先进的方法，将化学、细胞生物学和药理学与人类和动物的精神药理学联系起来，以解决这一问题。项目1将利用药物功能磁共振成像、动态因果建模和人类实验室任务来证明5-HT2R基因变异在可卡因依赖受试者中同时驱动冲动和线索反应性。项目2将使用啮齿动物模型来阐明5-HT2AR：5-HT2CR失衡，这种失衡驱动冲动和线索反应，并提供实验平台来正常化5-HT2AR：5-HT2CR动态平衡，降低复发的易感性。项目3将设计和合成具有5-HT2R靶向作用的双功能分子，以在动物模型中建立抗复发的概念验证疗效，并研究受体同分异构体的独特生物学。协同效应将通过细胞生物学和药理学核心产生，该核心将集中在人类中进行遗传筛选、体外细胞分析新配体、受体信号和体外定位以及受体同种和异构体的研究。行政核心将集中、协调和促进TASC的生产性社区，特别强调消除在翻译成瘾研究方面取得成功的障碍，优化指导经验，并向整个社区传达TASC和该领域的进展。TASC任务的进展将提供对药物依赖无序状态下的神经功能障碍的洞察，并建立5-HT2AR：5-HT2CR与靶向新配体的平衡恢复将修复体内平衡并减轻促进复发的有害行为。

DESCRIPTION (provided by applicant): Cocaine abuse and dependence continue to extract considerable personal, health and societal tolls in the U.S. and the world. The cycling progressive nature of this disorder stymies efforts to stay abstinent with relapse oft precipitated by impulsive behavior and craving in the face of exposure to cocaine-associated cues (cue reactivity). Serotonin (5-HT) neurotransmission is a strategic nexus that mechanistically connects these phenotypes. The Translational Addiction Sciences Center (TASC) is comprised of a translational team bridging from molecules to cells to animals to humans with the long-term research goal to definitively reveal the role of 5-HT in addiction neurobiology and to integrate this knowledge into the dominant theoretical constructs of addiction. The central research theme of the TASC is that impulsive action and cue reactivity are mechanistically-linked to disrupted 5-HT signaling through the 5-HT2A receptor (5-HT2AR) and 5-HT2CR localized to prefrontal-striatal-thalamic circuitry. Our premise is that restoration of the 5-HT2AR:5-HT2CR balance will repair corticostriatal deficits and ameliorate relapse. The TASC is led by an experienced, translational team that melds classical and state-of-the-art methodologies, bridging chemistry, cellular biology and pharmacology with human and animal psychopharmacology to address this problem. Project 1 will utilize pharmaco-fMRI, dynamic causal modeling, and human laboratory tasks to demonstrate that 5-HT2R gene variants drive both impulsivity and cue reactivity in cocaine-dependent subjects. Project 2 will employ rodent models to illuminate the 5-HT2AR:5-HT2CR imbalance that drives impulsivity and cue reactivity and to provide the experimental platform to normalize 5-HT2AR:5-HT2CR homeostasis and reduce vulnerability to relapse. Project 3 will design and synthesize bifunctional molecules with targeted actions at 5-HT2R to establish proof-of-concept efficacy against relapse in animal models and to study the unique biology of receptor homo- and heteromers. Synergy will be engendered through the Cellular Biology and Pharmacology Core which will centralize genetic screening in humans, cellular assays In vitro for new ligands, receptor signaling and localization ex vivo and studies of receptor homo- and heteromers. The Administrative Core will centralize, coordinate and facilitate the productive community of the TASC, with particular emphasis on removing barriers to success in translational addiction research, optimizing mentoring experiences, and communicating advances in the TASC and the field to the community at large. The progress of the TASC mission will provides insight Into neural dysfunction in the disordered state of drug dependence and establish that restoration of the 5-HT2AR:5-HT2CR balance with targeted new ligands will repair homeostasis and mitigate deleterious behaviors that promote relapse.