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: 9066619
• 负责人: SANDRA D COMER
• 金额: $ 20.42万
• 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/9066619
• 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; Health; 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; Mus; Neuraxis; Neuroglia; Neurotransmitters; Participant; Permeability; Pharmaceutical Preparations; Pilot Projects; Placebos; Procedures; Public Health; Questionnaires; Randomized; Rattus; 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 activation; glial cell development; high risk; inhibitor/antagonist; methamphetamine abuse; methamphetamine effect; methamphetamine use; multiple sclerosis patient; neurotoxic; novel; preclinical study; 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（由申请人提供）：滥用甲基苯丙胺是世界范围内严重的公共卫生问题，但没有有效的药物可以治疗这种疾病，兴奋剂使用障碍可能如此难以治疗的一个原因是它们会激活许多神经递质系统。目前的建议是检查血脑屏障（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点数据表明，米诺环素，一种广谱抗生素和神经胶质细胞活化抑制剂，可降低甲基苯丙胺破坏血脑屏障的能力。此外，丹麦开发的一项新技术表明，可以测量血脑屏障通透性的细微变化。称为动态对比​​增强磁共振成像（DCE-MRI）的技术尚未应用于药物滥用研究。本提案旨在确定是否可以检测到甲基苯丙胺引起的血脑屏障破坏。如果结果是积极的，未来的研究将探讨神经胶质抑制剂改变甲基苯丙胺引起的血脑屏障通透性变化的能力，参与者将在为期 9 天的住院研究期间居住在研究单位。在 2 天的区块中，按随机顺序在不同的日子服用活性甲基苯丙胺。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。在重复给药前和给药后的第二天，将评估参与者的扫描以及对药物的主观反应，参与者将有机会自行服用前一次接受的药物。具体目标 1 是使用 DCE-MRI 研究药物引起的 BBB 通透性变化。具体目标 2 是检查个体参与者的 BBB 通透性之间的潜在相关性。以及滥用倾向的衡量标准（主观反应和药物自我给药行为）。通过针对 BBB 而不是特定的神经递质系统，该研究有可能对当前对物质依赖治疗方法的思考产生重大影响。然而，这项研究的先例非常有限，并且所提出的 DCE-MRI 程序以前尚未使用过。瘾。