CNS VIRAL INJURY AND VULNERABILITY TO OPIATE DRUG ABUSE

描述：申请者摘要 获得性免疫缺陷综合症(艾滋病)和静脉药物滥用 重叠的流行病。重叠的程度增加了这样一种可能性 阿片类药物依赖的脆弱性可能直接或间接地与 病毒引起的中枢神经系统的神经化学和分子变化。目标是 这项建议的目的是研究病毒诱导的易感性变化 阿片类药物强化和依赖。使用一种小动物模型 慢性病毒性脑炎的神经病理与人类艾滋病毒相似 神经病理学，即病毒引起的内源性改变的假说 阿片类药物的表达与阿片类药物强化的行为效应有关 依赖性是可以测试的。一种持续性中枢神经系统病毒的动物模型 基于大鼠实验性博尔纳病病毒感染的感染 将开发并测试1)鸦片类药物的增强作用，如 通过静脉自服海洛因(特定目标1)和 2)阿片类药物的依赖诱导作用，由躯体测量 阿片类药物戒断的迹象，以及阿片类药物的情感(情绪)效应 用地点厌恶来衡量退缩(具体目标2)。神经学 阿片类药物敏感性改变的底物将通过检查确定 应用定量神经解剖学技术对富含阿片类物质的结构进行研究 (具体目标3)。最后，在体外，病毒的机制发生了改变 将通过检查阿片类药物的影响来调查阿片类药物的表达 病毒对转录活性宿主细胞蛋白的感染(特定目的 4)。这些研究将大大有助于阐明病毒诱导的神经 阿片类药物依赖的调节机制。关于病毒如何起作用的知识 对阿片类药物易感性的发展将提供新的见解 治疗和预防鸦片类药物滥用和一般药物滥用。 此MCSDA应用程序中提出的工作旨在提供培训 神经药理学、神经行为学、病毒学和分子生物学。这个 研究项目是在George Koob(博士)的帮助下开发的。的 斯克里普斯研究所(TSRI)和W.Ian Lipkin(M.D.)的 加州大学欧文分校(UCI)。该研究计划将考虑到 在几个学科中发展新的技能和技术： 学习利用药物滥用动物模型的方法，加上 分子、细胞培养和病毒制备技术。因为 建议的范围和多学科性质，工作将是 在TSRI和UCI联合进行。在授权期结束时， 具备行为药理学、神经药理学和 在药物研究和治疗方面继续工作的分子生物学 上瘾将会被候选人染上。

DESCRIPTION: Applicant's Abstract Acquired Immunodeficiency Syndrome (AIDS) and intravenous drug abuse are overlapping epidemics. The extent of overlap raises the possibility that vulnerability to opiate dependence may be directly or indirectly linked to virus-induced neurochemical and molecular changes in the CNS. The objective of this proposal is to study viral-induced changes in vulnerability to opiate reinforcement and dependence. Using a small animal model of a chronic viral encephalitis with neuropathologic similarities to human HIV neuropathology, the hypothesis that viral-induced changes in endogenous opioid expression are linked to behavioral effects on opiate reinforcement and dependence can be tested. An animal model of a persistent CNS viral infection based on experimental Borna disease virus infection of the rat will be developed then tested for 1) the reinforcing effects of opiates as measured by intravenous self-administration of heroin (Specific Aim 1) and 2) the dependence-inducing effects of opiates, as measured by the somatic signs of opiate withdrawal, and the affective (emotional) effects of opiate withdrawal as measured by place aversion (Specific Aim 2). The neural substrates for altered opiate sensitivity will be established by examination of opiate-rich structures using quantitative neuroanatomic techniques (Specific Aim 3). Finally, in vitro, the viral mechanisms for altered opioid expression will be investigated by examination of the effects of viral infection on transcriptionally active host cell proteins (Specific Aim 4). These studies will go far toward elucidating viral-induced neural mechanisms mediating opiate dependence. Knowledge of how viruses contribute to the development of vulnerability to opiate use will provide new insights into treatment and prevention of opiate abuse and drug abuse in general. The work proposed in this MCSDA application is designed to provide training in neuropharmacology, neurobehavior, virology, and molecular biology. The research program was developed with the assistance of George Koob (Ph.D.) of The Scripps Research Institute (TSRI) and W. Ian Lipkin (M.D.) of the University of California, Irvine (UCI). The research plan will allow for the development of new skills and techniques in several disciplines: the learning of methodologies utilizing animal models of drug abuse, plus molecular, cell culture and viral preparative techniques. Because of the scope and multidisciplinary nature of the proposal, the work will be conducted jointly at TSRI and UCI. At the conclusion of the grant period, the requisite skills in behavioral pharmacology, neuropharmacology and molecular biology for continued work in the study and treatment of drug addiction will have been acquired by the candidate.