PET & CSF STUDIES OF HUMANS EXPOSED TO MDMA (ECSTASY)

在动物中，娱乐性药物3，4-亚甲二氧基甲基苯丙胺（MDMA）是一种记录在案的5-羟色胺（5-HT）神经毒素。MDMA是否对人类也有神经毒性尚不清楚，但最近有证据表明它是，即， 人类MDMA使用者的脑脊液（CSF）中5-HT代谢物5-HIAA的浓度低于对照组。评估MDMA对人体神经毒性潜力的困难主要源于没有直接的方法来研究活体人脑中的神经元。 正电子发射断层扫描（PET）与5-HT神经元特异性的放射性配体结合使用时，是一种成像技术，可用于研究人一生中5-HT神经元的状态。事实上，初步观察表明，新开发的5-HT转运蛋白配体[11 C] McN-5652的PET成像可用于检测MDMA损伤狒狒的脑5-HT缺陷。该项目的总体目标是证实这一发现并将其扩展到人类。为了实现这一目标，提出了两个系列的研究，一个在狒狒和人类。在临床前研究中，狒狒将被MDMA或2 '-NH2-MPTP（MPTP类似物）损伤，当与去甲基米帕明（DMI）一起给药时，对大脑5-HT神经元具有高度和选择性毒性。已知MDMA损伤整个前脑中的脑5-HT系统，使用MDMA损伤的狒狒将用于"受试者间"比较; 2'-NH2-MPTP损伤的狒狒将用于"受试者内"比较，2'-NH2-MPTP应允许脑5-HT系统单侧损伤。在损伤后36周和72周，动物将接受[11 C] McN-5652 PET研究，并进行腰椎穿刺以测定CSF 5-HIAA。然后处死动物，直接测定组织5-HT轴突标志物。这些研究将提供独特的机会来研究通过PET在体内测量的特异性[11 C] McN-5652结合的改变与组织5HT神经元标志物的变化之间的关系，即，5-HT、5-HIAA、[3H]西酞普兰结合位点，直接在相同动物的死后组织中测量。在第二组研究中，具有广泛的MDMA使用史，但至少四周没有药物的人类将接受与狒狒相同的PET和CSF研究。将MDMA使用者（MDMA组，n = 18）中获得的结果与使用MDMA以外药物的个体（非MDMA组，n = 18）以及无药物使用或依赖史的受试者（非药物组，n = 18）中获得的结果进行比较。这些研究的目的是进一步评估暴露于MDMA后人类中枢5-HT神经元的状态，并将观察结果扩展至人类，即在非人灵长类动物中，[11 C] McN-5652 PET成像可用于检测MDMA诱导的5-HT神经损伤。本项目的长期目标是：1）进一步验证[11 C] McN-5652在用PET研究活体人脑中5-HT神经元中的有用性; 和2）更好地确定MDMA对人类的神经毒性潜力。

In animals, the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is a documented serotonin (5-HT) neurotoxin. Whether or not MDMA us 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 in assessing the neurotoxic potential of MDMA in humans stems largely from the fact that there are not direct methods for investigating 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 druing 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, MPTP analog that, when administered with desmethylimipramine (DMI), is highly and selectively toxic to the brain 5- HT neurons. Baboons lesioned with MDMA which is known to damage brain 5-HT systems in the entire forebrain, will 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" comparisons. 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 study the relationship between alterations in specific [11C]McN-5652 binding measured in vivo by means of PET and changes in tissue 5HT 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 an extensive history of MDMA use, but drug-free for at least four 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 use 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.