DOPAMINE TRANSPORTER BINDING POTENTIAL INCREASES WITH AN ACUTE DOSE OF MDMA

多巴胺转运蛋白结合潜力随急性剂量的 MDMA 增加

• 批准号: 8172882
• 负责人: Bertha K Madras
• 金额: $ 1.81万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172882
• 关键词: Acute; Altropane; Binding; Brain; Cerebellum; Computer Retrieval of Information on Scientific Projects Database; Corpus striatum structure; Dose; Funding; Generations; Grant; Hour; Human; Image; Injection of therapeutic agent; Institution; Intramuscular; Ligands; Macaca mulatta; Measures; Mediating; Methods; Pharmaceutical Preparations; Positron-Emission Tomography; Property; Psychotropic Drugs; Research; Research Personnel; Resources; Route; Serotonin; Source; Time; United States National Institutes of Health; base; carbene; dopamine transporter; ecstasy; expectation; in vivo; interest; neurochemistry; nonhuman primate; prevent; serotonin transporter

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. AIMS: MDMA methylene-dioxymethamphetamine or ecstasy is a widely abused psychoactive drug, considered to produce its empathic effects primarily by modulating serotonin transporter SERT function and brain serotonin activity. MDMA is also a mild psychomotor stimulant in humans and nonhuman primates, an effect reportedly mediated by dopaminergic activity. We previously demonstrated that MDMA is an effective substrate for the dopamine DAT transporter. Based on these findings, we hypothesized that an acute dose of MDMA would occupy the DAT in vivo, as manifest by reduced DAT binding potential. METHODS: In rhesus monkeys n=5, we used PET imaging and the DAT ligand (11C)CFT to measure DAT binding potential. PET imaging was performed over 60 min, with regions of interest drawn over striatum and cerebellum and binding potential calculated using the SSRT method. Following generation of baseline DAT binding potential, MDMA (1.5 mg/kg was injected intravenously and imaging was repeated 1 hour after drug injection. RESULTS: Contrary to expectations, DAT binding potential measured with (11C)CFT was consistently higher, 121 percent (n=5, than baseline values, following an acute dose of MDMA. Intramuscular MDMA and the DAT ligand (11C)altropane yielded inconsistent changes, confirming our previous findings that METH effects are sensitive to route of administration and time. CONCLUSIONS: These unanticipated findings are conceivably attributable to neurochemical properties of METH or technical reasons. MDMA may alter DAT regulatory mechanisms acutely to increase DAT availability or alternately, MDMA blockade of striatal SERT could prevent SERT occupancy by (11C)CFT to increase PET ligand availability for the DAT.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目标：MDMA亚甲基二氧基甲基苯丙胺或摇头丸是一种广泛滥用的精神活性药物，被认为主要通过调节5-羟色胺转运体SERT功能和大脑5-羟色胺活性来产生移情作用。MDMA在人类和非人类灵长类动物中也是一种轻度精神兴奋剂，据报道这种作用是由多巴胺能活性介导的。我们以前证明了MDMA是多巴胺DAT转运蛋白的有效底物。基于这些发现，我们假设急性剂量的MDMA会占据体内DAT，表现为DAT结合潜力降低。方法：在恒河猴n=5，我们使用PET成像和DAT配体（11 C）CFT来测量DAT结合潜力。PET成像进行超过60分钟，与感兴趣的区域绘制在纹状体和小脑和结合电位使用SSRT方法计算。 在产生基线DAT结合潜力后，静脉注射MDMA（1.5 mg/kg），并在药物注射后1小时重复成像。研究结果：与预期相反，在急性剂量的MDMA后，用（11 C）CFT测量的DAT结合潜力始终高于基线值121%（n=5）。肌肉注射MDMA和DAT配体（11 C）altropane产生不一致的变化，证实了我们以前的研究结果，即METH的影响是敏感的给药途径和时间。结论：这些意料之外的发现可以归因于METH的神经化学性质或技术原因。MDMA可能会急剧改变DAT调节机制，以增加DAT的可用性，或者MDMA阻断纹状体SERT可以阻止（11 C）CFT占用SERT，以增加DAT的PET配体可用性。