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

甲基苯丙胺、压力和 SIV：对血脑屏障和淋巴结的影响

• 批准号: 7678911
• 负责人: JOHN P CAPITANIO
• 金额: $ 64.74万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678911
• 关键词: Acquired Immunodeficiency Syndrome; Adrenergic Agents; Albumins; Amphetamine Abuse; Autopsy; Basal Ganglia; Blood; Blood - brain barrier anatomy; Cannabis; Cells; Disease; Drug usage; Fibrinogen; Frequencies; Gene Expression; Genes; HIV; HIV Infections; Impairment; Infection; Inflammatory; Interferon Type I; Interferon-alpha; Interferons; Leukocytes; Lymphoid Tissue; Methamphetamine; Monkeys; Neurocognitive; Norepinephrine; North America; Pattern; Peripheral Nerves; Permeability; Plasma; Play; Precipitating Factors; Prevalence; Process; Property; Recombinant Interferon Beta; Research; Role; SIV; Serum; Site; Staining method; Stains; Stress; Sympathomimetics; Tight Junctions; Up-Regulation; Varicosity; Viral; Viral Load result; adrenergic; beta-adrenergic receptor; chemokine; cytokine; density; frontal lobe; high risk sexual behavior; lymph nodes; monocyte; nerve supply; neuropsychological; receptor expression; social stress

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

说明（由申请方提供）：在全世界，甲基苯丙胺等兴奋剂的使用人数仅次于大麻，在北美，苯丙胺滥用流行率是全球流行率的两倍。甲基苯丙胺（冰毒）也被发现在艾滋病中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害有累加效应。冰毒是一种拟交感神经药，可引起外周神经释放去甲肾上腺素，我们已经证明去甲肾上腺素可促进HIV和SIV的复制。因此，甲基苯丙胺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。甲基苯丙胺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。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诱发因素）和艾滋病毒/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累加效应，导致血液传播因子（如感染的单核细胞和炎性细胞因子）穿过BBB的运输增加，从而导致CNS感染和损伤以及神经心理学损害的可能性更大。最后，考虑到我们所证明的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看到的额外影响，我们建议β肾上腺素能受体阻断剂或重组干扰素β的施用将消除甲基苯丙胺和淋巴结中压力的影响。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复制和血液中疾病相关指标的改变中所起的作用; 2）检查甲基苯丙胺和应激在改变SIV感染猴的血脑屏障通透性中所起的作用; 3）检查β肾上腺素能受体阻断剂或重组干扰素-β的施用是否会消除甲基苯丙胺在淋巴结和BBB中的作用。