PET IMAGING STUDY OF BRAIN VMAT2 IN HUMAN METHAMPHETAMINE USERS

描述(申请人提供)：甲基苯丙胺使用者脑VMAT2的PET成像研究目的。我们的主要目标是获得人类甲基苯丙胺(MA)使用者的脑成像数据，这些数据可能有助于开发囊泡性单胺转运体(VMAT2)作为生物标志物来解释病理生理学并指导临床医生对吸毒者进行更适当的治疗干预。VMAT2是人类大脑中负责单胺类神经递质包装的突触囊泡转运体，主要定位于人纹状体中的多巴胺能终末，现已被建议作为一种新的工具来研究精神刺激剂使用者的囊泡多巴胺状态。背景资料。目前，对兴奋剂MA成瘾尚无有效的治疗方法。尽管有争议，但我们认为大脑缺乏神经递质多巴胺，正如我们在大脑中发现的那样，可能是MA使用者的一些行为(特别是认知)问题的原因。然而，缺乏表明MA使用者存在多巴胺缺乏的体内数据。在对MA使用者的试点正电子发射断层扫描(PET)研究中，我们意外地发现，纹状体(+)-[11C]DTBZ与VMAT2的结合在早期戒断期间增加，这一发现可以用多巴胺(在一些MA使用者中减少)和(+)-[11C]DTBZ与VMAT2结合的竞争减少来解释。作为泡状多巴胺状态的体内生物标记物，可能有助于为MA使用者选择最合适的治疗，需要在具有代表性的受试者中证实这些发现，并在纵向研究中确定早期戒断时结合水平是否下降。具体的目标、设计和假设。我们主要的特异性目标是通过PET成像来测量具有代表性的慢性MA使用者的纹状体(+)-[11C]DTBZ结合，每个使用者在最后一次使用药物后的4-7天、12-15天和28-30天进行评估，并在匹配的对照组中进行。根据我们的试验数据，我们的主要工作假设是，在MA使用者非常早期(4-7天)戒断的过程中，纹状体(+)-[11C]DTBZ的结合将高于正常，而在较晚的戒断(30天)后，水平可能会恢复正常。意义重大。我们的研究由在人类和实验动物中拥有广泛VMAT2专业知识的研究人员设计和执行，是旨在开发一种脑生物标记物的第一步，该标记物可能会识别哪些MA使用者可以从多巴胺替代药物中受益。此外，这些发现可能提供独特的信息，有助于在神经学应用中解释脑成像VMAT2数据，该生物标记物已被提议用于评估神经保护剂的有效性。

DESCRIPTION (provided by applicant): PET IMAGING STUDY OF BRAIN VMAT2 IN HUMAN METHAMPHETAMINE USERS OBJECTIVE. Our broad goal is to obtain brain imaging data in human methamphetamine (MA) users that could help in development of the vesicular monoamine transporter (VMAT2) as a biomarker to explain pathophysiology and guide clinicians to more appropriate treatment interventions in the drug users. VMAT2 is the synaptic vesicle transporter responsible for monoamine neurotransmitter packaging in human brain, is predominantly localized to dopaminergic terminals in human striatum, and is now proposed in this application as a new tool to investigate vesicular dopamine status in psychostimulant users. BACKGROUND. At present there exists no useful treatment for addiction to the stimulant MA. Although controversial, we believe that a brain deficiency of the neurotransmitter dopamine, as suggested by our postmortem brain findings, might be responsible for some of the behavioural (especially cognitive) problems of MA users. However, in vivo data suggesting dopamine deficiency in MA users are lacking. In a pilot positron emission tomography (PET) study of MA users we discovered, unexpectedly, that striatal (+)- [11C]DTBZ binding to VMAT2 was increased during early abstinence, a finding which can be explained by decreased competition between dopamine (reduced in some MA users) and (+)-[11C]DTBZ binding to VMAT2. As an in vivo biomarker of vesicular dopamine status might be helpful in selecting the most appropriate treatment for MA users, there is need to confirm these findings in a representative number of subjects and establish in a longitudinal study whether binding levels do or do not decline in early abstinence. SPECIFIC AIM, DESIGN, AND HYPOTHESIS. Our major SPECIFIC AIM is to measure by PET imaging striatal (+)-[11C]DTBZ binding in a representative number of chronic MA users, with each user assessed at 4-7, 12-15, and 28-30 days following last use of the drug, and in a matched control group. Based on our pilot data, our major working HYPOTHESIS is that striatal (+)-[11C]DTBZ binding will be above normal in MA users during very early abstinence (4-7 days) and that levels might normalize in later abstinence (30 days). SIGNIFICANCE. Our study, designed and executed by investigators with extensive VMAT2 expertise in both the human and experimental animal, is a first step aimed at developing a brain biomarker that might identify those MA users who could receive benefit from dopamine substitution medication. In addition, the findings could provide unique information that could help interpretation of brain imaging VMAT2 data in neurology applications for which this biomarker has been proposed to assess efficacy of neuroprotective agents.