OPIOD - DOPAMINE INTERACTIONS IN COCAINE ABUSE

这是对导师研究科学家发展奖(KO1)的请求。这项拟议的研究旨在阐明由于接触可卡因而导致的阿片系统和多巴胺系统之间的关系。我们所知道的可卡因对内源性阿片系统的影响大部分是基于在老鼠身上进行的调查。然而，这些研究可能与人类滥用可卡因的相关性有限，因为大鼠和人脑中阿片受体的表达存在差异，以及这些物种之间的神经解剖学和神经化学差异。此外，自我给药对阿片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和多巴胺受体的神经适应。拟议研究的主要重点是训练正电子发射断层扫描(PET)成像，以绘制随着时间的推移，由于可卡因自我给药和丁丙诺啡治疗方案而发生的大脑受体功能的变化。PET的优点之一是，这些参数可以在相同的受试者中进行纵向评估，从而减少动物间研究中固有的误差。用PET获得的数据将直接与用PET分析的相同受试者以及在相同条件下处理的动物组中使用体外放射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，这些治疗对阿片受体功能激活的影响也将用[35S]GTPGammaS放射自显影方法来评估，该方法用于识别受体激活的G蛋白。这一建议的一个主要优点是利用不同的实验方法来评估受体的功能和解剖分布，这些方法相互补充。该项目的多学科性质将在罗伯特·马赫博士的指导下进行，并与灵长类动物行为、阿片/可卡因药理学和信号转导专业的教员合作，将为候选人提供一个独特的机会来解决有关可卡因的长期影响的问题。因此，该项目将使候选人能够在人口稀少的灵长类神经生物学领域发展成为一名独立的调查员，研究可卡因滥用长期影响的神经生物学底物。

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.