MDMA Neurotoxicity and 5HT-Glutamate Interactions

描述(由申请人提供)： 鉴于目前3，4-亚甲基二氧基甲基苯丙胺(MDMA)滥用的增加，了解其滥用所导致的选择性5-羟色胺(5HT)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-羟色胺神经毒性的影响。具体地说，拟议的实验将检验5-羟色胺调节海马区谷氨酸传输的改变能力。以前的工作表明，高剂量的MDMA减少了海马区5-羟色胺传递的神经元标记物，但没有描述这种5-羟色胺神经毒性的神经化学后果。这项研究计划将包括双探针活体微透析和高效液相色谱-电化学法的培训。具体目的1将确定MDMA诱导的5-羟色胺神经毒性通过抑制海马区5-羟色胺传递的减少和中缝背核(DRN)自身抑制的增加而增强海马区谷氨酸传递的能力。由于海马区容易受到应激的损害，因此，特定目标2将研究MDMA诱导的5-羟色胺神经毒性与急、慢性应激协同作用的可能性，以进一步增强海马区谷氨酸的传递，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-羟色胺神经毒性可能在MDMA滥用者中发生的一些长期功能后果，并开始解决可能解释MDMA滥用者所报告的各种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.