The amphetamine analog 3,4- methylenedioxymethamphetamine (MDMA) continues to be a popular drug of abuse despite evidence in animals and humans that this agent produces long-term toxicity to serotonin (5-HT) neurons. However, beyond this well-established finding, the mechanisms through which MDMA produces 5-HT neurotoxicity remain unknown. Several lines of evidence suggest that oxidative stress contributes to the process of MDMA-induced 5-HT toxicity. The intent of the present study is to elucidate the processes, proceeding or subsequent to, the induction of oxidative stress that are the determinants of MDMA-induced 5-HT neurotoxicity. A central focus of this application is the hypothesis that MDMA toxicity in the hippocampus, in contrast to the striatum, results, in part, from excessive extracellular concentrations of glutamate. Specifically, it is hypothesized that the long-term depletion of 5-HT produced by MDMA in the hippocampus results from a glutamate-mediated increase in nitric oxide formation and a subsequent impairment of mitochondrial function. Impaired mitochondrial function provides a feed forward mechanism for the further generation of free radicals and ensuing structural damage to 5-HT terminals and depletion of 5-HT.
The specific aims of the proposal are to utilize in vivo microdialysis, biochemical experiments and immunohistochemical studies to: 1) assess the contribution of glutamate to the process of MDMA toxicity in the hippocampus and establish the mechanism underlying the MDMA-induced increase in extracellular glutamate, 2) evaluate potential mechanisms through which MDMA increases nitric oxide formation, 3) determine whether increased nitric oxide formation contributes to the MDMA-induced inhibition of mitochondrial function and 4) assess the extent and mechanism by which MDMA promotes the cleavage of the cytoskeletal proteins tau and spectrin. The linkage of the processes of oxidative damage and mitochondrial impairment to the long-term effects of MDMA on 5-HT terminals has significant implication for drug-induced neurodegeneration and risks this may pose to human health.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007427-16
Application #
7816725
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (02))
Program Officer
Frankenheim, Jerry
Project Start
1992-03-15
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
16
Fiscal Year
2010
Total Cost
$297,012
Indirect Cost
Name
University of Cincinnati
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Huff, Courtney L; Morano, Rachel L; Herman, James P et al. (2016) MDMA decreases glutamic acid decarboxylase (GAD) 67-immunoreactive neurons in the hippocampus and increases seizure susceptibility: Role for glutamate. Neurotoxicology 57:282-290
Collins, Stuart A; Huff, Courtney; Chiaia, Nicolas et al. (2016) 3,4-methylenedioxymethamphetamine increases excitability in the dentate gyrus: role of 5HT2A receptor-induced PGE2 signaling. J Neurochem 136:1074-84
Collins, Stuart A; Gudelsky, Gary A; Yamamoto, Bryan K (2015) MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors. Eur J Pharmacol 761:95-100
Anneken, John H; Cunningham, Jacobi I; Collins, Stuart A et al. (2013) MDMA increases glutamate release and reduces parvalbumin-positive GABAergic cells in the dorsal hippocampus of the rat: role of cyclooxygenase. J Neuroimmune Pharmacol 8:58-65
Huff, Courtney; Bhide, Nirmal; Schroering, Allen et al. (2013) Effect of repeated exposure to MDMA on the function of the 5-HT transporter as assessed by synaptosomal 5-HT uptake. Brain Res Bull 91:52-7
Anneken, John H; Gudelsky, Gary A (2012) MDMA produces a delayed and sustained increase in the extracellular concentration of glutamate in the rat hippocampus. Neuropharmacology 63:1022-7
Schaefer, Tori L; Grace, Curtis E; Skelton, Matthew R et al. (2012) Neonatal citalopram treatment inhibits the 5-HT depleting effects of MDMA exposure in rats. ACS Chem Neurosci 3:12-21
Darvesh, Altaf S; Carroll, Richard T; Geldenhuys, Werner J et al. (2011) In vivo brain microdialysis: advances in neuropsychopharmacology and drug discovery. Expert Opin Drug Discov 6:109-127
Yamamoto, Bryan K; Moszczynska, Anna; Gudelsky, Gary A (2010) Amphetamine toxicities: classical and emerging mechanisms. Ann N Y Acad Sci 1187:101-21
Schaefer, T L; Grace, C E; Gudelsky, G A et al. (2010) Effects on plasma corticosterone levels and brain serotonin from interference with methamphetamine-induced corticosterone release in neonatal rats. Stress 13:469-80

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