PET AND CSF STUDIES OF HUMANS EXPOSED TO METHYLENEDIOXYMETHAMPHETAMINE

在动物身上，娱乐药物3，4-亚甲基二氧基甲基苯丙胺(MDMA) 是一种记录在案的5-羟色胺(5-HT)神经毒素。无论MDMA是否也是 对人类的神经毒性尚不清楚，但最近有证据表明 IS，即人类MDMA使用者的5-羟色胺代谢物浓度较低 脑脊液(CSF)中5-HIAA水平明显高于对照组。困难在于 评估MDMA对人类的神经毒性潜力很大程度上源于 事实上，没有直接的方法来调查 活体人脑中的5-羟色胺神经元。正电子发射断层扫描 (PET)，当与5-羟色胺的特异性放射性配基结合使用时 神经元，是一种可以用来研究这种状态的成像技术 人类生命中5-羟色胺神经元的数量。事实上，初步观察到 建议使用新开发的5-羟色胺转运体配体进行PET成像 [11C]MCN-5652可用于检测MDMA患者的脑组织5-羟色胺缺陷 这些是狒狒。该项目的总体目标是确认这一发现并 把它推广到人类身上。 为了实现这一目标，提出了两个系列的研究，一个是在狒狒身上的研究 另一种是在人类身上。在临床前研究中，狒狒将被损毁 使用MDMA或2‘-NH2-MPTP，一种MPTP类似物，当给药时 去甲基米帕明(DMI)，对大脑有高度和选择性的毒性 5-羟色胺神经元。服用MDMA的狒狒，已知会损害大脑 整个前脑中的5-羟色胺系统，将用于“受试者之间” 比较；使用2‘-NH2-MPTP损毁的狒狒，这应该允许 单侧脑部5-羟色胺系统病变，将用于 受试者的比较。在损伤后36周和72周，动物 将接受[11C]MCN-5652的正电子发射计算机断层扫描和腰椎穿刺术检查脑脊液 5-HIAA测定。然后这些动物将被牺牲以直接 组织5-羟色胺轴突标志物的测定。这些研究将提供 独一无二的机会探索在特定的变化之间的关系 [11C]用PET法测定MCN-5652的体内结合及组织变化 5-羟色胺神经元标记物，即5-羟色胺、5-羟IAA、[~3H]西酞普兰结合部位， 直接在相同动物的死后组织中测量。 在第二组研究中，有广泛使用MDMA历史的人类， 但停药至少4周，将接受PET和脑脊液检查 与狒狒中的完全相同。在MDMA用户(MDMA组， N=18)将与使用 MDMA以外的药物(非MDMA组，n=18)以及获得的药物 在没有药物滥用或依赖史的受试者中(非吸毒组， N=18)。这些研究的目的是进一步评估 人中枢5-羟色胺神经元在MDMA暴露后，并延伸到 人类在非人灵长类动物中进行PET成像的观察 [11C]MCN-5652可用于检测MDMA诱导的5-羟色胺神经损伤 在生活中。 该项目的长期目标是：1)进一步验证 {11C]MCN-5652在活体5-羟色胺神经元研究中的应用 2)更好地确定MDMA的神经毒性潜力 在人类身上。

In animals, the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is a documented serotonin (5-HT) neurotoxin. Whether or not MDMA is also neurotoxic in humans is not known, but there is recent evidence that it is, i.e. human MDMA users have lower concentrations of the 5-HT metabolite 5-HIAA in their cerebrospinal fluid (CSF) than controls. The difficulty is assessing the neurotoxic potential of MDMA in humans stems largely from the fact that there are no direct methods for investigating the status of 5-HT neurons in the living human brain. Positron emission tomography (PET), when used in conjunction with a radioligand specific for the 5-HT neuron, is an imaging technique that could be used to study that status of 5-HT neurons in humans during life. Indeed, preliminary observations suggest that PET imaging with the newly developed 5-HT transporter ligand [11C]McN-5652 is useful for detecting brain 5-HT deficits in MDMA-lesioned baboons. The overall goal of the project is to confirm this finding and extend it to humans. To achieve this goal, two series of studies are proposed, one in baboons and the other in humans. In preclinical studies, baboons will be lesioned with either MDMA or 2'-NH2-MPTP, an MPTP analog that, when administered with desmethylimipramine (DMI), is highly and selectively toxic to brain 5-HT neurons. Baboons lesioned with MDMA, which is known to damage brain 5-HT systems in the entire forebrain, wil be used for "between subjects" comparisons; baboons lesioned with 2'-NH2-MPTP, which should permit unilateral lesions of brain 5-HT systems, will be used for "within subjects" comparisions. At 36 and 72 weeks after lesioning, the animals will undergo PET studies with [11C]McN-5652 and lumbar punctures for CSF 5-HIAA determinations. The animals will then be sacrificed for direct determination of tissue 5-HT axonal markers. These studies will offer the unique opportunity to explore the relation between alterations in specific [11C]McN-5652 binding measured in vivo by means PET and changes in tissue 5-HT neuronal markers, i.e., 5-HT, 5-HIAA, [3H]citalopram binding sites, measured directly in postmortem tissue of the same animals. In a second set of studies, humans with a history of extensive MDMA use, but drug-free for at least 4 weeks, will undergo PET and CSF studies identical to those in baboons. Results obtained in MDMA users (MDMA group, n=18) will be compared to those obtained in individuals who have used drugs other than MDMA (non-MDMA group, n=18), as well as to those obtained in subjects without a history of drug abuse or dependence (non-Drug group, n=18). The purpose of these studies is to further assess the status of central 5-HT neurons in humans after MDMA exposure, and to extend to humans the observation that in nonhuman primates PET imaging with [11C]McN-5652 is useful for detecting MDMA-induced 5-HT neural injury during life. The long-term goals of this project are: 1) to further validate the usefulness of{11C]McN-5652 for studying 5-HT neurons in the living human brain with PET; and 2) to better define the neurotoxic potential of MDMA in humans.