TREATMENT OF ADDICTIONS--BIOLOGICAL CORRELATES

描述（由申请人提供）： 海洛因、可卡因和酒精成瘾，无论是单独的还是混合的，沿着其频繁的医学并发症，包括B和C型肝炎、艾滋病和精神并发症，仍然是我们国家和世界上许多地方面临的主要医学问题。有效的治疗必须建立在对每一种特定成瘾性疾病的生物学基础的基本理解的基础上，包括接触滥用药物的影响。我们的NIH-NIDA治疗研究中心将继续识别和研究成瘾的分子，神经生物学，遗传和其他生物学相关性，重点关注内源性阿片系统的作用，以及可能影响治疗结果的因素。在我们正在进行的中心的延续建议中，所有实验室和临床研究都是在互动的基础上开发的，依靠中心进行整合。双向转化研究是该中心工作的标志。基础和应用临床研究的研究结果和观察结果用于制定实验室研究中进行测试的特定假设。相反，实验室研究的结果将在可行和适当的情况下尽快应用于临床研究，然后应用于临床。拟开展的具体项目包括：1）长期阿片类药物和可卡因、戒断和激发对内源性阿片类药物和相关神经递质系统的超微结构、受体和基因表达的影响; 2）阿片类药物和可卡因对应激反应下丘脑-垂体-肾上腺轴的分子生物学和表达的影响; 3）阿片类药物和相关神经肽的生物转化和药效学：多巴胺能功能和可卡因效应的调节; 4）阿片类药物和可卡因的神经内分泌效应：内源性阿片类药物和成瘾性疾病中的应激反应的作用;和5）阿片类药物和可卡因滥用中涉及的阿片受体的条件性敲除。科学项目将通过八个研究核心资源进行整合，包括一个研究培训核心，加强互动，以促进只有一个中心才能提供的协同作用。由于培训和信息传播活动的增加，我们建议将P50专业中心改为P60综合中心。

DESCRIPTION (provided by applicant): Heroin, cocaine, and alcohol addictions, alone and in combination, along with their frequent medical complications, including hepatitis B and C, AIDS, and psychiatric comorbidity, remain the major medical problems confronting our nation and much of the world. Effective treatments must be based on a fundamental understanding of the biological basis of each specific addictive disease, including the effects of exposure to drugs of abuse. Our NIH-NIDA Treatment Research Center will continue to identify and study the molecular, neurobiological, genetic and other biological correlates of the addictions, with focus on the role of the endogenous opioid system, and also factors which might affect treatment outcome. In this proposal for the continuation of our ongoing Center, all laboratory and clinical research studies have been developed on an interactive basis, relying upon the Center for their integration. Bidirectional translational research is the hallmark of the work of the Center. Research findings and observations from basic and applied clinical research are used to formulate specific hypotheses to be tested in laboratory research. Conversely, findings from laboratory research will be applied as promptly as feasible and appropriate, into clinical research, and then to the clinic. The specific projects proposed include: 1) effects of chronic opiates and cocaine, withdrawal, and challenge, on ultrastructure, receptors and gene expression of the endogenous opioid and related neurotransmitter systems; 2) effects of opiates and cocaine on the molecular biology and expression of the stress responsive hypothalamic-pituitary-adrenal axis; 3) biotransformation and pharmacodynamics of opioid and related neuropeptides: modulation of dopaminergic function and cocaine effects; 4) neuroendocrine effects of opiates and cocaine: role of the endogenous opioids and stress responsivity in addictive diseases; and 5) a conditional knockout of glutamatergic receptors involved in opioid and cocaine abuse. Scientific projects will be integrated through the eight Research Core resources, including a Research Training core, strengthening interactions to foster the synergism which only a Center can provide. We propose changing our P50 Specialized Center to a P60 Comprehensive Center because of increased training and information dissemination activities.