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Studies on the 3,4-methylenedioxymethamphetamine (MDMA)-induced dysregulation of energy metabolism and its neurochemical consequences

Darvesh, Altaf Sultan
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1115150433

Abstract Details

2005, PhD, University of Cincinnati, Pharmacy : Pharmaceutical Sciences.
3,4-Methylenedioxymethamphetamine (MDMA), an analog of the amphetamine class, is a psychostimulant and a popular drug of abuse. MDMA is considered to be selectively neurotoxic to serotonergic nerve terminals in different brain regions, however the exact mechanisms through which MDMA produces serotonin (5-HT) neurotoxicity remain unknown. Oxidative stress has been reported to play an important role in mediating this process. In addition to the potential role of oxidative stress in MDMA neurotoxicity, there is evidence that bioenergetic stress may play an important role in the toxicity produced by amphetamine analogs. The overall hypothesis, which provides the basis for the current proposal is that MDMA produces dysregulation of brain energy metabolism and this plays an important role in MDMA-induced neurotoxicity.The effect of MDMA on brain energy metabolism was investigated by examining the effect of MDMA on brain glycogen. MDMA produced a time and dose-dependent decrease in brain glycogen. Maintenance of rats at a cool ambient temperature of 17 0C or pretreatment with 5-HT2 antagonists, significantly attenuated the MDMA-induced hyperthermia and glycogenolysis. However, MDMA-induced hyperthermia, as well as glycogenolysis, was found to be neither sufficient nor necessary for the MDMA-induced long-term 5-HT depletion.Administration of substrates of energy metabolism, e.g., nicotinamide, ubiquinone, attenuated the MDMA-induced long-term 5-HT depletion. Nicotinamide also attenuated the long-term DA and 5-HT depletion produced by coperfusion of MDMA and the mitochondrial inhibitor malonate. A neurotoxic regimen of MDMA produced a significant depletion of ATP in the striatum and hippocampus. Dysregulation of energy metabolism and energy depletion results in increased intracellular Ca2+ levels in the mitochondria, which results in activation of nitric oxide synthase (NOS) and generation of nitric oxide (NO). A neurotoxic regimen of MDMA produced an increase in NO in the striatum. The MDMA and malonate-induced long-term DA and 5-HT depletion were attenuated by administration of NOS inhibitors, as well as a peroxynitrite decomposition catalyst. The neuronal NOS inhibitor S-methyl-L-thiocitrulline (S-MTC) attenuated the MDMA-induced long-term 5-HT depletion without attenuating the MDMA-induced hyperthermia.These results support the conclusion that MDMA produces dysregulation of energy metabolism and this bioenergetic stress contributes to MDMA-induced neurotoxicity.
Dr. Gary Gudelsky (Advisor)
179 p.
Health Sciences, Pharmacy
3,4-Methylenedioxymethamphetamine; Neurotoxicity; Serotonin; Oxidative stress; Bioenergetic stress; Energy metabolism

Recommended Citations

Citations

  • Darvesh, A. S. (2005). Studies on the 3,4-methylenedioxymethamphetamine (MDMA)-induced dysregulation of energy metabolism and its neurochemical consequences [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1115150433

    APA Style (7th edition)

  • Darvesh, Altaf. Studies on the 3,4-methylenedioxymethamphetamine (MDMA)-induced dysregulation of energy metabolism and its neurochemical consequences. 2005. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1115150433.

    MLA Style (8th edition)

  • Darvesh, Altaf. "Studies on the 3,4-methylenedioxymethamphetamine (MDMA)-induced dysregulation of energy metabolism and its neurochemical consequences." Doctoral dissertation, University of Cincinnati, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1115150433

    Chicago Manual of Style (17th edition)

ucin1115150433
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© 2005, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.