OPIOD - DOPAMINE INTERACTIONS IN COCAINE ABUSE

这是一个指导研究科学家发展奖（KO 1）的请求。 这项研究旨在阐明阿片系统和多巴胺系统之间的关系，作为暴露于可卡因的结果。 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大鼠中进行的研究。 然而，这些研究可能与人类可卡因滥用的相关性有限，因为大鼠与人脑中阿片受体表达的差异，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，以评估伴随可卡因滥用灵长类动物模型中可卡因自我给药的阿片和多巴胺受体的神经适应性。 拟议研究的主要重点是正电子发射断层扫描（PET）成像的培训，以绘制可卡因自我给药和丁丙诺啡治疗方案后随时间推移发生的脑受体功能变化。 PET的优势之一是可以在相同受试者中纵向评价这些参数，从而减少动物间研究中固有的误差。 将使用PET获得的数据直接与使用体外放射自显影技术在使用PET分析的相同受试者以及在相同条件下处理的动物组中分析的数据进行比较。 由于受体KD和BMAX值的变化并不总是与这些受体的功能活化相关，因此还将采用用于鉴定受体活化G蛋白的[35 S] GTP γ S放射自显影法评估这些治疗对阿片受体功能活化的影响。 这一建议的一个主要优势是利用不同的实验方法，相互补充，以评估受体的功能和解剖分布。 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来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为人口稀少的灵长类神经生物学竞技场的独立调查员，以调查可卡因滥用长期影响的神经生物学基础。

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.