NDMA NEUROTOXICITY--PERMANENT OR TRANSIENT

（+/-）3，4-亚甲二氧基甲基苯丙胺（MDMA）是一种娱乐性药物， 有记录的对脑5-羟色胺（5-HT）具有神经毒性活性的滥用 神经元虽然MDMA的急性神经毒性作用已被证实， 由于其特征，关于MDMA对5-HT的长期影响知之甚少 神经元在啮齿类动物中，有迹象表明5-HT神经元恢复，但 复苏的程度、模式和持续时间仍不确定。 在 非人灵长类动物，倾向于维持更严重的5-HT神经元损伤 比啮齿类动物，恢复也被观察到，但在过去的研究 项目期间表明，恢复是不正常的， 取决于大脑区域。具体来说，似乎大脑区域 最初引起更严重损伤，远离5-HT神经细胞 中缝中的小体，或者离5-HT轴突束更远（例如，背 新皮质），无法恢复。相比之下， 严重影响，更接近中缝，或旁边的主要5-HT 轴突束（例如，下丘脑），往往完全恢复，往往过度。 这种持续的大脑区域去神经支配的模式， 其他人的神经支配或过度神经支配表明，在某些情况下， 在这种情况下，MDMA损伤可能导致持久的重组， 上行5-HT轴突投射。拟议的总体目标 研究的目的是更全面地描述5-HT轴突的这些变化， 投射模式，并探测可能的功能后果。 该项目的具体目标是：（1）进一步描述 在灵长类动物中，MDMA诱导的神经再支配模式改变;（2）确认和 扩展初步观察，这些轴突的变化是 与部分损失的多巴胺能神经细胞体在 脑干的吻侧中缝核;（3）确定功能 在非人中MDMA诱导的多巴胺能神经毒性的后果 灵长类动物结合定量放射自显影，神经化学， 免疫组化方法将用于进一步表征 改变5-HT神经支配模式。此外，这些方法将 用于确定异常神经支配模式是否受到 初始MDMA损伤的严重程度，如果持续时间超过 18-到目前为止，研究的药物后生存期。初裁决定 5-HT免疫反应性神经细胞体损失将通过测定 是否可以在额外的MDMA处理猴中证实，以及 确定它是否可以用不同的5-HT神经元证实 标记（例如，针对色氨酸羟化酶的抗体）和 替代方法（银变性）。此外， 神经细胞损失可以通过使用更强烈的MDMA方案来增强 将被探索。 MDMA神经毒性的可能功能后果 将通过检查5-HT神经支配的变化是否 与以下改变相关：1）神经内分泌功能; 2）敏感性 3）获得一种 定时任务;或4）昼夜活动模式。与以往一样，长期 这项研究的目的是描述长期的 MDMA在灵长类动物中的神经病理学作用，并更好地定义 5-HT在中枢神经系统中的作用

(+/-)3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug of abuse with documented neurotoxic activity towards brain serotonin (5-HT) neurons. Although the acute neurotoxic effects of MDMA have been well characterized, little is known about the long-term effects of MDMA on 5-HT neurons. In rodents, there is indication that 5-HT neurons recover, but the extent, pattern and duration of the recovery remain uncertain. In nonhuman primates, which tend to sustain more severe 5-HT neuronal injury than rodents, recovery is also observed, but research during the past project period suggests that the recovery is abnormal, and highly dependent on brain region. Specifically, it appears that brain regions that initially incur more severe damage, are distant from 5-HT nerve cell bodies in the raphe, or are farther from 5-HT axon bundles (e.g., dorsal neocortex), fail to recover. In contrast, brain regions that are less severely affected, are closer to the raphe, or are next to a major 5-HT axon tract (e.g., hypothalamus), tend to recover fully, often excessively. This pattern of lasting denervation of some brain regions, with reinnervation or hyperinnervation of others suggests that, under some circumstances, MDMA injury can lead to a lasting reorganization of ascending 5-HT axonal projections. The overall goal of the proposed studies is to more fully characterize these changes in 5-HT axonal projection patterns, and to probe for possible functional consequences. The specific aims of the project are to: (1) Further characterize the altered reinnervation pattern induced by MDMA in primates; (2) Confirm and extend the preliminary observation that these axonal changes are associated with a partial loss of serotonergic nerve cell bodies in the rostral raphe nuclei of the brain stem; and (3) Identify functional consequences of MDMA-induced serotonergic neurotoxicity in nonhuman primates. A combination of quantitative autoradiographic, neurochemical, and immunohistochemical methods will be used to further characterize the altered 5-HT innervation pattern. In addition, these same methods will be used to determine if the aberrant innervation pattern is influenced by the severity of the initial MDMA injury, and if it persists longer than the 18-month post-drug survival thus far studied. The preliminary finding of 5-HT-immunoreactive nerve cell body loss will be pursued by determining whether it can be confirmed in additional MDMA-treated monkeys, and by ascertaining whether it can be substantiated with different 5-HT neuronal markers (e.g., antibody directed against tryptophan hydroxylase) and alternate methods (silver degeneration). Further, the possibility that nerve cell loss can be enhanced through use of more intense MDMA regimens will be explored. Possible functional consequences of MDMA neurotoxicity will be investigated by examining whether changes in 5-HT innervation are associated with alterations in: 1) neuroendocrine function; 2) sensitivity to the behavioral effects of serotonergic drugs; 3) acquisition of a timing task; or 4) circadian activity patterns. As before, the long-term objectives of this research are to characterize the long-term neuropathologic effects of MDMA in primates and to better define the functional role of 5-HT in the CNS.