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人数仅次于大麻，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（冰毒）在艾滋病中也扮演着越来越重要的角色。有证据表明，甲基苯丙胺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性影响。甲基苯丙胺是一种拟交感神经引起从周围神经释放去甲肾上腺素，我们已经证明去甲肾上腺素促进HIV和SIV复制。甲基安非他明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后果，导致更多的病毒复制和更高的病毒载量，以及更多的循环感染细胞（主要是单核细胞）可以进入中枢神经系统。甲基苯丙胺对中枢神经系统的影响也可能源于对血脑屏障（BBB）的影响。独立的证据表明，冰毒、压力（包括冰毒在内的许多药物使用的一个促成因素）和艾滋病毒/SIV都有助于削弱血脑屏障。我们认为，这三个因素可能具有叠加效应，导致血源性因素（如感染单核细胞和炎症细胞因子）在血脑屏障中的运输增加，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增加。最后，考虑到我们已经证明的应激对淋巴结病毒复制的影响，以及我们预期由于甲基苯丙胺的拟交感神经特性而看到的额外影响，我们提出β肾上腺素能受体阻断或重组干扰素- β的管理将消除甲基苯丙胺和应激在淋巴结中的影响。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SIV复制和血液中疾病相关指标的改变中所起的作用；2)研究甲基苯丙胺和应激在改变SIV感染猴子血脑屏障通透性中的作用；3)研究阻断β肾上腺素能受体或给予重组干扰素β是否会消除甲基苯丙胺在淋巴结和血脑屏障中的作用。相关性

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