Dynamic Contrast-Enhanced MRI to Measure Blood-Brain Barrier Permeability in Substance Abusers

 描述（由申请人提供）：滥用甲基苯丙胺是一个严重的公共卫生问题，但没有有效的药物治疗这种疾病。兴奋剂使用障碍之所以如此难以治疗，原因之一是它们激活了许多神经递质系统。本提案的目标是检查血脑屏障（BBB），而不是特定的神经递质系统，作为药物开发的可能目标。在小鼠中收集的令人兴奋的新试验数据表明，米诺环素，一种广谱抗生素和胶质细胞活化抑制剂，降低了甲基苯丙胺破坏BBB的能力。此外，丹麦针对多发性硬化症患者开发的一项新技术表明，可以测量BBB渗透性的细微变化。这种技术被称为动态对比增强磁共振成像（DCE-MRI），尚未应用于药物滥用的研究。本提案旨在确定是否可以在甲基苯丙胺滥用者中检测到甲基苯丙胺诱导的血脑屏障破坏。如果结果是积极的，未来的研究将提出检查神经胶质抑制剂的能力，改变甲基苯丙胺诱导的血脑屏障通透性的变化。参与者将在为期9天的住院研究期间居住在研究单位。他们将在2天区组期间的不同日期以随机顺序接受活性或安慰剂甲基苯丙胺。在每个2天区块的第一天，参与者将接受安慰剂或活性甲基苯丙胺。将在给药前和给药后重复评估DCE-MRI扫描以及对药物的主观反应。在每个2天区组的第二天，受试者将有机会自行给药前一天接受的药物。具体目的1是使用DCE-MRI研究药物诱导的BBB通透性变化。我们假设，甲基苯丙胺将增加血脑屏障通透性相对于安慰剂。具体目标2是检查个体参与者的BBB渗透性与滥用倾向（主观反应和药物自我给药行为）测量之间的潜在相关性。我们假设BBB渗透性将与积极主观反应的增加幅度以及MA自我给药直接相关。这项拟议的研究测试了一个非常新颖的假设，该假设有可能通过靶向BBB而不是特定的神经递质系统，对目前关于物质依赖治疗方法的想法产生实质性影响。然而，本研究的先例非常有限，并且所提出的DCE-MRI程序以前未用于成瘾。

 DESCRIPTION (provided by applicant): Abuse of methamphetamine is a serious public health concern worldwide but no effective medications exist for treating this disorder. One reason that stimulant use disorders may be so difficult to treat is that they activate numerous neurotransmitter systems. The goal of the present proposal is to examine the blood-brain barrier (BBB), rather than a specific neurotransmitter system, as a possible target for medications development. Exciting new pilot data collected in mice showed that minocycline, a broad-spectrum antibiotic and inhibitor of glial cell activation, decreased the ability of methamphetamine to disrupt the BBB. In addition, a new technique developed in Denmark in patients with multiple sclerosis showed that it is possible to measure subtle changes in BBB permeability. This technique, called dynamic contrast-enhanced magnetic resonance imaging (DCE- MRI), has not yet been applied to studies of substance abuse. The present proposal is designed to determine whether methamphetamine-induced disruptions in the BBB can be detected in methamphetamine abusers. If the results are positive, future studies will be proposed to examine the ability of glial inhibitors to alter methamphetamine-induced changes in BBB permeability. Participants will reside on a research unit during a 9- day inpatient study. They will receive in randomized order either active or placebo methamphetamine on separate days during 2-day blocks. On the first day of each 2-day block, participants will receive placebo or active methamphetamine. DCE-MRI scans, as well as subjective responses to drug, will be assessed both before and repeatedly after drug administration. On the second day of each 2-day block, participants will be given the opportunity to self-administer the drug that they had received the previous day. Specific Aim 1 is to investigate drug-induced changes in BBB permeability using DCE-MRI. We hypothesize that methamphetamine will increase BBB permeability relative to placebo. Specific Aim 2 is to examine the potential correlation between BBB permeability in individual participants and measures of abuse liability (subjective responses and drug self-administration behavior). We hypothesize that BBB permeability will be directly correlated with increased magnitude of positive subjective responses, as well as MA self- administration. The proposed study tests a highly novel hypothesis, which has the potential to substantially impact current thinking about treatment approaches to substance dependence, by targeting the BBB rather than a specific neurotransmitter system. However, there is very limited precedent for this study and the proposed DCE-MRI procedure has not been used previously in addiction.