MDMA alters immunity to infections of the peripheral and central nervous systems

描述（由申请人提供）：青少年和年轻人是最有可能滥用被称为“俱乐部毒品”的越来越多的化合物的年龄组。摇头丸，或称3,4亚甲基二氧甲基苯丙胺（MDMA），是目前最受俱乐部滥用的毒品之一，我们刚刚开始了解这种药物对这些年轻人中枢神经系统功能的有害影响。虽然我们怀疑某些疾病与俱乐部药物滥用之间存在联系，但还没有研究调查摇头丸是否会对中枢神经系统或周围微生物疾病的免疫功能产生如此有害的影响。这有点令人惊讶，因为3,4-亚甲基二氧甲基苯丙胺是年轻人最常滥用的药物之一。此外，摇头丸的主要作用是中枢神经系统，它可以诱发社会行为，从而增加接触各种疾病的可能性。目前的提议将使用小鼠模型来研究3,4-亚甲基二氧甲基苯丙胺如何改变宿主对病毒感染的保护性反应。具体而言，本提案将研究3,4-亚甲基二氧甲基苯丙胺在体内或体外滥用该药物暴露后调节白细胞免疫反应的能力。药理学研究将使人们了解3,4-亚甲基二氧基甲基苯丙胺可能发挥其作用的机制。将特别注意微量胺受体介导机制的重要性。此外，3,4-亚甲基二氧甲基苯丙胺及其代谢物对白细胞功能的直接影响将通过纯化细胞培养进行评估，随后评估细胞因子和趋化因子的分泌和细胞表面分子的表达。补充研究将在病毒感染小鼠的组织上进行。这些研究将确定俱乐部药物摇头丸调节感染后炎症反应的机制，并首次将摇头丸的使用与年轻人疾病恶化联系起来。

DESCRIPTION (provided by applicant): Teenagers and young adults are the age group most likely to abuse a growing list of compounds known as "club drugs". Ecstasy, or 3,4 methylenedioxymethamphetamine (MDMA), is currently one of the most popular club drugs of abuse, and we are just beginning to learn about the deleterious effects this drug can have on central nervous system function of these young adults. While we suspect there is a link between some diseases and club drug abuse, there have been no studies to investigate whether Ecstasy might have such a deleterious effect on immune function within the central nervous system or in the periphery during microbial diseases. This is somewhat surprising, since 3,4- methylenedioxymethamphetamine is one of the most commonly abused drugs by young adults. Furthermore, Ecstasy has its primary effects on the central nervous system and can induce the very social behaviors that would increase the likelihood of exposure to various diseases. The present proposal will use mouse models to investigate how 3,4-methylenedioxymethamphetamine can alter the protective host response to a viral infection. Specifically, this proposal will investigate the ability of 3,4-methylenedioxymethamphetamine to modulate the immune response of leukocytes following in vivo or in vitro exposure of this drug of abuse. Pharmacological studies will allow an understanding of the mechanims by which 3,4-methylenedioxymethamphetamine might exert its effects. Particular attention will be given to the importance of trace amine receptor-mediated mechanisms. In addition, the direct effects of 3,4-methylenedioxymethamphetamine and its metabolites on leukocyte function will be assessed using cultures of purified cells followed by an evaluation of cytokine and chemokine secretion and expression of cell surface molecules. Complementary studies will be performed on tissues from mice with a viral infection. These studies will define mechanisms by which the club drug, Ecstasy, can modulate inflammatory responses following infection, and represent the first effort to link the use of Ecstasy with exacerbated diseases of young adults.