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. ? ? ?
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