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

动态对比增强 MRI 测量药物滥用者的血脑屏障渗透性

• 批准号: 8989439
• 负责人: SANDRA D COMER
• 金额: $ 21.38万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989439
• 关键词: Abstinence; Amphetamine Abuse; Antibiotics; Applications Grants; Astrocytes; Award; Basic Science; Behavior; Behavioral; Blood - brain barrier anatomy; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Contrast Media; Corpus striatum structure; Data; Denmark; Development; Diffusion; Disease; Dose; Double-Blind Method; Drug abuse; Event; Extravasation; Future; Gadolinium; Goals; Hour; Human; Imaging Techniques; Immune; Individual; Individual Differences; Inflammatory Response; Inpatients; Laboratories; Lead; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Methamphetamine; Methods; Microglia; Minocycline; Modeling; Monitor; Multiple Sclerosis; Mus; Neuraxis; Neuroglia; Neurotransmitters; Participant; Patients; Permeability; Pharmaceutical Preparations; Pilot Projects; Placebos; Procedures; Public Health; Questionnaires; Randomized; Rattus; Relative (related person); Research; Self Administration; Self-Administered; Substance Addiction; Substance abuse problem; Surface; System; Techniques; Testing; Thinking; Visual; Work; addiction; analog; cell motility; contrast enhanced; design; dopaminergic neuron; drug abuser; drug seeking behavior; gadolinium oxide; glial cell development; high risk; inhibitor/antagonist; methamphetamine abuse; methamphetamine use; neurotoxic; novel; preclinical study; public health relevance; response; substance abuser; tool; treatment trial

 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.

 描述（由适用提供）：滥用甲基苯丙胺是全球严重的公共卫生问题，但没有有效治疗这种疾病的有效药物。刺激性使用障碍可能很难治疗的原因之一是它们激活了许多神经递质系统。本提案的目的是研究血脑屏障（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，米诺环素是一种广谱抗生素和神经胶质细胞激活的抑制剂，可降低甲基苯丙胺破坏BBB的能力。此外，丹麦在多发性硬化症患者中开发的一种新技术表明，可以测量BBB渗透性的细微变化。该技术称为动态对比​​增强的磁共振成像（DCE-MRI），尚未应用于药物滥用的研究。本提案旨在确定甲基苯丙胺诱导的BBB中的破坏是否可以在甲基苯丙胺滥用器中检测到。如果结果是阳性的，则将提出未来的研究来检查神经胶质抑制剂改变甲基苯丙胺诱导的BBB渗透性变化的能力。参与者将在9天的住院研究中居住在研究部门。他们将在2天的街区中的不同日子内以随机顺序或安慰剂甲基苯丙胺接收。在每个2天街区的第一天，参与者将获得安慰剂或活跃的甲基苯丙胺。 DCE-MRI扫描以及对药物的受试者反应，将在药物给药之前和反复评估。在每2天街区的第二天，将有机会自我管理他们前一天收到的药物。具体目的1是使用DCE-MRI研究药物诱导的BBB渗透性变化。我们假设甲基苯丙胺相对于安慰剂会增加BBB的渗透性。具体目标2是检查个别参与者中BBB渗透性与虐待责任措施（主观反应和药物自我管理行为）之间的潜在相关性。我们假设BBB的渗透性将与阳性幅度增加直接相关。主观反应以及MA自我管理。拟议的研究检验了一个高度新颖的假设，该假设有可能通过靶向BBB而不是特定的神经递质系统来实质性地影响目前对物质依赖治疗方法的思维。但是，这项研究的先例非常有限，而拟议的DCE-MRI程序先前尚未用于成瘾。