OPIOD - DOPAMINE INTERACTIONS IN COCAINE ABUSE

阿片 - 多巴胺与可卡因滥用的相互作用

• 批准号: 6041698
• 负责人: JAMES B DAUNAIS
• 金额: $ 11.26万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6041698
• 关键词: G protein; Macaca mulatta; biological signal transduction; buprenorphine; cocaine; dopamine; dopamine receptor; drug abuse; drug interactions; endogenous opioid; laboratory rat; longitudinal animal study; opioid receptor; positron emission tomography; receptor binding; receptor expression; self medication

This is a request for a Mentored Research Scientist Development Award (KO1). The proposed research is designed to elucidate the relationship between the opioid system and the dopamine system as a result of exposure to cocaine. The majority of what we know of cocaine's effects on the endogenous opioid system has been based on investigations carried out in rats. These studies may be of limited relevance however, to cocaine abuse in humans, because of the differences in expression of opioid receptors in rat vs human brain, as well as, neuroanatomical and neurochemical differences between these species. Moreover, the effects of self-administration on opioid receptors are largely unknown. A strategy combining in vivo and in vitro imaging methods is proposed to assess neuroadaptations in opioid and dopamine receptors that accompany cocaine self-administration in a primate model of cocaine abuse. The primary focus of the proposed studies is training in positron emission tomography (PET) imaging to map changes in brain receptor function that occur over time as a consequence of cocaine self-administration and in response to a buprenorphine treatment regimen. One of the strengths of PET is that these parameters can be evaluated longitudinally within the same subjects thereby reducing error that is inherent in a between animal study. The data obtained with PET will be directly compared to data analyzed using in vitro autoradiographic techniques in the same subjects analyzed with PET as well as in groups of animals treated under identical conditions. Because alterations in receptor KD and BMAX values do not always correlate with functional activation of those receptors, the effects of these treatments on functional activation of opioid receptors will also be assessed with the [35S]GTPgammaS autoradiographic method which is used to identify receptor-activated G-proteins. A major strength of this proposal is the utilization of different experimental approaches that complement each other to assess the functional and anatomical distribution of receptors. The multidisciplined nature of this project, which will be conducted under the mentorship of Dr. Robert Mach, and in collaboration with faculty specializing in primate behavior, opioid/cocaine pharmacology and signal transduction, will provide a unique opportunity for the candidate to address issues regarding the long-term effects of cocaine. This project will thus enable the candidate to develop into an independent investigator in the sparsely populated arena of primate neurobiology to investigate the neurobiological substrates underlying the long-term effects of cocaine abuse.

这是指导研究科学家发展奖（KO1）的要求。 拟议的研究旨在阐明阿片类药物系统与多巴胺系统之间的关系。 我们对可卡因对内源性阿片类药物系统的影响所了解的大多数是基于在大鼠中进行的研究。 然而，这些研究可能与人类中可卡因滥用的相关性有限，因为这些物种之间的大鼠与人脑的表达差异以及神经解剖学和神经化学差异。 此外，自我管理对阿片类药物受体的影响在很大程度上是未知的。 提出了一种结合体内和体外成像方法的策略，以评估在可卡因滥用的灵长类动物模型中伴随可卡因自我给药的阿片类和多巴胺受体中的神经适应。 拟议研究的主要重点是训练正电子发射断层扫描（PET）成像以绘制大脑受体功能的变化，这是由于可卡因自我给药而随着时间的流逝而发生的，并响应丁丙诺啡治疗方案。 PET的优势之一是可以在同一受试者中纵向评估这些参数，从而减少动物研究之间固有的误差。 使用PET获得的数据将直接与使用PET以及在相同条件下接受治疗的动物组中的同一受试者中使用体外自显影技术分析的数据进行比较。 由于受体KD和BMAX值的改变并不总是与这些受体的功能激活相关，因此这些治疗对阿片受体功能激活的影响也将使用[35S] GTPGAMMAS自载体自显影方法评估，该方法用于识别受体激活的G蛋白。 该建议的主要优势是利用不同的实验方法，这些方法相互补充以评估受体的功能和解剖分布。 该项目的跨学科性质将在罗伯特·马赫（Robert Mach）博士的指导下进行，并与专门从事灵长类动物行为，阿片类药物/可卡因药理学和信号转导的教师合作，将为候选人提供一个独特的机会，以解决有关可卡因长期影响的问题。因此，该项目将使候选人能够发展成稀疏的灵长类动物神经生物学领域的独立研究者，以研究可卡因滥用的长期影响的神经生物学基质。