MDMA Neurotoxicity and 5HT-Glutamate Interactions

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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.