MDMA Neurotoxicity and 5HT-Glutamate Interactions

描述（由申请人提供）： 鉴于目前滥用3，4-亚甲二氧基甲基苯丙胺（MDMA）的情况有所增加，了解滥用MDMA导致的选择性5-羟色胺（5-HT）神经毒性的机制和长期后果至关重要。总体目标是深入了解MDMA介导的5 HT神经毒性的影响。具体而言，拟议的实验将检查5 HT调节海马中谷氨酸传输的能力改变。以前的研究表明，高剂量的MDMA减少海马体中5 HT传递的神经元标记物，但尚未描述这种5 HT神经毒性的神经化学后果。这项研究计划将涉及双探针体内微透析和HPLC-EC的培训。具体目标1将确定MDMA诱导的5 HT神经毒性通过由海马中5 HT传递减少和中缝背核（DRN）中自抑制增加介导的去抑制来增强海马中谷氨酸传递的能力。由于海马易受应激损伤，因此特定目标2将研究MDMA诱导的5 HT神经毒性与急性和慢性应激协同作用的潜力，以进一步增强海马谷氨酸传递并促进谷氨酸介导的兴奋性毒性。拟议的研究将阐明MDMA诱导的5-HT神经毒性可能发生在MDMA滥用者中的一些长期功能后果，并开始讨论可能解释MDMA滥用者中各种报告的记忆缺陷的神经机制。

DESCRIPTION (provided by applicant): Given the current rise in abuse of 3,4-methylenedioxymethamphetamine (MDMA), understanding the mechanisms and long-term consequences of the selective serotonin (5HT) neurotoxicity that results from its abuse is critical. The overall objective is to provide insight into the effects of MDMA-mediated 5HT neurotoxicity. Specifically, the proposed experiments will examine the altered ability of 5HT to modulate glutamate transmission in the hippocampus. Previous work has shown that high doses of MDMA decrease neuronal markers of 5HT transmission in the hippocampus, but has stopped short of delineating the neurochemical consequences of this 5HT neurotoxicity. This research proposal will involve training in dual probe in vivo microdialysis and HPLC-EC. Specific Aim 1 will determine the ability of MDMA-induced 5HT neurotoxicity to augment glutamate transmission in the hippocampus through disinhibition mediated by a decrease in 5HT transmission in the hippocampus and increased autoinhibition in the dorsal raphe nucleus (DRN). Since the hippocampus is vulnerable to damage produced by stress, Specific Aim 2 will examine the potential for MDMA-induced 5HT neurotoxicity to synergize with acute and chronic stress to further augment hippocampal glutamate transmission and to promote glutamate-mediated excitotoxicity. The proposed studies will elucidate some of the long-term functional consequences of MDMA-induced 5HT neurotoxicity that may occur in MDMA abusers and begin to address the neural mechanisms that may explain the variety of reported memory deficits evident in MDMA abusers.