Methamphetamine Abuse, Inhibitory Control: Implications for Treatment

描述(由申请人提供)：尽管对药物滥用和依赖的科学理解取得了进展，但缺乏有效的治疗方法，迫切需要针对这些疾病的新疗法。拟议的P20资助的成瘾转化研究开发中心将通过整合临床前研究直接为成瘾临床研究提供信息，并补充利用临床见解帮助确定基础科学方法的目标，来满足这一需求。拟议的中心将在成瘾的神经生物学成分知识方面做出重大贡献的基础科学家与处于治疗研究前沿的临床研究人员联系起来。该发展中心的主题将是作为甲基苯丙胺(MA)依赖的治疗目标的抑制控制受损。我们之所以做出这一选择，是因为：a)全球MA滥用问题的严重性；b)其后果的严重性；c)缺乏对MA依赖的有效治疗；d)削弱对药物成瘾的抑制性控制的重要性；以及e)我们在促进对MA滥用的理解和治疗方面的领导地位。在这个最初的重点，我们提出了四个相互关联的项目，以表征由于甲基苯丙胺(MA)暴露在人类和动物模型中的行为、神经系统和神经化学水平上的反应抑制损伤，并评估这些缺陷的药物调节。P20中心的四个研究项目旨在：1)描绘MA依赖受试者抑制控制缺陷的潜在神经回路；2)利用MA自我给药的人体实验室模型，将抑制控制缺陷与吸毒行为联系起来；3)建立和表征(从行为和神经化学上)非人类灵长类动物模型，以研究MA滥用的抑制控制缺陷特征；以及4)表征旨在调节MA依赖啮齿动物模型中反应抑制的药物操纵的局部脑神经化学效应。如果每个项目都被设计成一个独立的研究，在中心环境之外，这四个项目以一种不可行的方式整合在一起。该中心将支持这些科学项目，总体目标是为跨学科翻译研究创造一个环境，使动物模型和人体实验室基础研究的信息流能够迅速应用于药物滥用治疗的开发，并制定研究职业发展计划，以协调和加强现有的培训计划，为博士后和博士后研究员和教职员工提供多种绝佳的机会，启动专注于药物滥用神经生物学研究的翻译方法的新项目。

DESCRIPTION (provided by applicant): Despite advances in the scientific understanding of drug abuse and dependence, effective treatments are lacking, and new therapies for these disorders are urgently needed. The proposed P20- funded Developmental Center for Translational Research on Addictions will address this need by integrating preclinical studies to directly inform clinical research on drug addiction, and complementarily, leveraging clinical insights to help target basic science approaches. The proposed Center links basic scientists who have made significant contributions to knowledge of the neurobiological components of addiction with clinical investigators who are at the forefront in treatment research. The theme of the developmental center will be impaired inhibitory control as a therapeutic target for methamphetamine (MA) dependence. We made this choice because of: a) the magnitude of the MA abuse problem worldwide; b) the severity of its consequences; c) the lack of an effective treatment for MA dependence; d) the importance of impaired inhibitory control to drug addiction; and e) our leadership in advancing the understanding and treatment of MA abuse. With this initial focus, we propose four interrelated projects to characterize impairments in response inhibition consequent to methamphetamine (MA) exposure at behavioral, neural systems, and neurochemical levels in both human and animal models, and to assess the pharmacological modulation of these deficits. The four research projects in this P20 Center aim: 1) to delineate the neural circuitry underlying deficits in inhibitory control in MA-dependent human subjects; 2) to relate deficits in inhibitory control to drug-taking behavior using a human laboratory model of MA self administration; 3) to establish and characterize (behaviorally and neurochemically) a non-human primate model for investigating inhibitory control deficits characteristic of MA abuse; and 4) to characterize regional brain neurochemical effects of pharmacological manipulations aimed at modulating response inhibition in a rodent model for MA dependence. The four projects are integrated in a way that would not be feasible if each project had been designed to be a discrete study, outside the Center environment. The Center will support these scientific projects with the over-arching goals of creating an environment for interdisciplinary translational research, whereby the flow of information from basic research in animal models and human laboratory studies can be rapidly applied to development of treatments for drug abuse, and developing a program of research career development that will coordinate and enhance existing training programs, providing multiple, excellent opportunities for pre- and postdoctoral fellows and faculty to initiate new projects focusing on translational approaches to studies of the neurobiology of drug abuse.