CNS VIRAL INJURY AND VULNERABILITY TO OPIATE DRUG ABUSE

描述：申请人摘要 获得性免疫缺陷综合症（艾滋病）和静脉注射药物滥用是 重叠流行病。 重叠的程度增加了一种可能性， 易受阿片剂依赖性的影响可能直接或间接与以下因素有关： 病毒诱导的CNS神经化学和分子变化。 客观 这项建议的一个重要目的是研究病毒引起的脆弱性变化， 阿片强化和依赖。 使用一个小动物模型， 神经病理学与人类HIV相似的慢性病毒性脑炎 神经病理学，假设病毒诱导的内源性变化 阿片样物质的表达与阿片样物质强化的行为效应有关 依赖性是可以检验的。 持续性CNS病毒感染的动物模型 基于大鼠实验博尔纳病病毒感染的感染 将开发，然后测试1）鸦片制剂的强化作用， 通过静脉自我注射海洛因（特定目标1）进行测量， 2)阿片类药物的依赖性诱导作用，通过体细胞测量， 阿片类药物戒断的迹象，以及阿片类药物的情感（情绪）影响 通过位置厌恶（具体目标2）测量的退缩。 神经 阿片敏感性改变的底物将通过检查 使用定量神经解剖学技术 （具体目标3）。 最后，在体外，病毒机制的改变， 阿片样物质的表达将通过检查 病毒对转录活性宿主细胞蛋白的感染（特异性目的 4）。 这些研究将大大有助于阐明病毒诱导的神经细胞凋亡。 介导阿片依赖的机制。 了解病毒如何 对阿片类药物使用的脆弱性的发展将提供新的见解 用于治疗和预防阿片类药物滥用和一般药物滥用。 本MCSDA申请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。 的 研究计划是在乔治库布（博士）的帮助下开发的。的 斯克里普斯研究所（TSRI）和W。Ian Lipkin（医学博士）的 加州尔湾大学（UCI）。 该研究计划将允许 发展若干学科的新技能和技术： 学习利用药物滥用动物模型的方法， 分子、细胞培养和病毒制备技术。 因为 范围和多学科性质的建议，工作将是 在TSRI和UCI联合进行。 在补助期结束时， 行为药理学，神经药理学和 分子生物学继续研究和治疗药物 候选人会上瘾。

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.