Methamphetamine, Stress and SIV: Effects at Blood-Brain Barrier and Lymph Nodes

描述（由申请人提供）：在世界范围内，甲基苯丙胺等兴奋剂的使用者数量仅次于大麻，而在北美，苯丙胺滥用的流行率是全球的两倍。人们发现甲基苯丙胺 (meth) 在艾滋病中也发挥着越来越重要的作用。有证据表明，冰毒和艾滋病毒感染对神经认知障碍和中枢神经系统损伤具有累加效应。冰毒是一种拟交感神经药，会导致周围神经释放去甲肾上腺素，我们已经证明去甲肾上腺素会促进 HIV 和 SIV 的复制。那么，冰毒对中枢神经系统的影响可能是其从次级淋巴组织的交感静脉曲张中释放去甲肾上腺素的能力的间接结果，导致更大的病毒复制和更高的病毒载量，以及更多数量的循环感染细胞（主要是单核细胞）可以进入中枢神经系统。冰毒对中枢神经系统的影响也可能是由于对血脑屏障 (BBB) 的影响造成的。独立的证据表明，冰毒、压力（许多药物使用的诱发因素，包括甲基苯丙胺）和 HIV/SIV 都可能导致血脑屏障的削弱。我们认为这三个因素可能具有相加效应，导致血源性因子（例如受感染的单核细胞和炎症细胞因子）穿过血脑屏障的运输增加，从而导致中枢神经系统感染和损伤以及神经心理损伤的可能性更大。最后，鉴于我们已证实压力对淋巴结中病毒复制的影响，以及我们预期由于甲基苯丙胺的拟交感神经特性而出现的额外影响，我们建议阻断β肾上腺素能受体或施用重组干扰素-β将消除甲基苯丙胺和压力在淋巴结中的影响。我们的具体目标是 1) 检查甲基苯丙胺和应激在神经支配模式、I 型干扰素基因表达、淋巴结中 SIV 复制以及血液中疾病相关指标改变中所起的作用； 2) 检查甲基苯丙胺和应激在改变 SIV 感染猴血脑屏障通透性方面的作用； 3) 检查β肾上腺素能受体阻断或施用重组干扰素-β是否会消除甲基苯丙胺在淋巴结和血脑屏障中的作用。

DESCRIPTION (provided by applicant): Worldwide, stimulants such as methamphetamine rank second only to cannabis in number of users, and in North America, the prevalence of amphetamine abuse is double the global rate. Methamphetamine (meth) is being found to play an increasingly important role in AIDS, as well. Evidence suggests that meth and HIV infection have additive effects on neurocognitive impairment and CNS damage. Meth is a sympathomimetic causing release of norepinephrine from peripheral nerves, and we have shown that norepinephrine promotes HIV and SIV replication. Meth's effects on the CNS, then, could be an indirect consequence of its ability to release norepinephrine from sympathetic varicosities in secondary lymphoid tissue, leading to greater viral replication and higher viral loads, and greater numbers of circulating, infected cells (primarily monocytes) that can enter the CNS. Meth's effects in the CNS could also result from effects on the blood-brain barrier (BBB). Independent lines of evidence suggest that meth, stress (a precipitating factor for much drug use, including methamphetamine), and HIV/SIV can all contribute to weakening the blood-brain barrier. We propose that these three factors could have additive effects, resulting in increased transport across the BBB of blood borne factors such as infected monocytes and inflammatory cytokines, leading to a greater likelihood of CNS infection and damage, and neuropsychological impairment. Finally, given our demonstrated effects of stress on viral replication in lymph nodes, and the additional effects we anticipate seeing due to the sympathomimetic properties of methamphetamine, we propose that beta adrenergic receptor blockade or administration of recombinant interferon-beta will abrogate the effects of methamphetamine and stress in the lymph node. Our specific aims are 1) to examine the role played by methamphetamine and stress in alterations in innervation patterns, Type I interferon gene expression, and SIV replication in lymph nodes, and disease-related indicators in blood; 2) to examine the role played by methamphetamine and stress in altering permeability of the blood-brain barrier in SIV infected monkeys; 3) to examine whether beta adrenergic receptor blockade or administration of recombinant interferon-beta will abrogate the effects of methamphetamine in lymph nodes and at the BBB.Relevance