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

 描述(申请人提供)：滥用甲基苯丙胺是世界范围内一个严重的公共卫生问题，但目前还没有有效的药物来治疗这种疾病。兴奋剂使用障碍很难治疗的一个原因是它们激活了许多神经递质系统。本提案的目标是研究血脑屏障(BBB)，而不是特定的神经递质系统，作为药物开发的可能靶点。在小鼠身上收集的令人兴奋的新的试验数据表明，米诺环素，一种广谱抗生素和神经胶质细胞激活的抑制剂，降低了甲基苯丙胺破坏血脑屏障的能力。此外，丹麦在多发性硬化症患者身上开发的一项新技术表明，有可能测量血脑屏障通透性的细微变化。这项技术被称为动态对比增强磁共振成像(DCE-MRI)，尚未被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引起的血脑屏障紊乱。如果结果是肯定的，将提出未来的研究，以检查胶质细胞抑制剂改变甲基苯丙胺诱导的血脑屏障通透性变化的能力。在为期9天的住院研究中，参与者将住在一个研究单位。他们将按随机顺序在两天内的不同日期接受活性或安慰剂甲基苯丙胺。在每个为期两天的疗程的第一天，参与者将接受安慰剂或活性甲基苯丙胺。DCE-MRI扫描以及对药物的主观反应将在给药前和给药后重复进行评估。在每个为期两天的封闭期的第二天，参与者将有机会自行给药，他们前一天收到的药物。具体目的1是利用DCE-MRI研究药物引起的血脑屏障通透性的变化。我们假设与安慰剂相比，甲基苯丙胺会增加血脑屏障的通透性。具体目标2是检查个体参与者的血脑屏障渗透性与滥用责任措施(主观反应和药物自我给药行为)之间的潜在相关性。我们假设血脑屏障通透性将与积极主观反应的增加以及MA自我管理的增加直接相关。这项拟议的研究测试了一种非常新颖的假说，该假说通过针对血脑屏障而不是特定的神经递质系统，有可能对目前关于物质依赖治疗方法的想法产生重大影响。然而，这项研究的先例非常有限，而且所建议的DCE-MRI程序以前还没有用于成瘾。

 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.