The Role of Metabolism in Ecstasy-Mediated Serotonergic Neurotoxicity

Persistent Link:
http://hdl.handle.net/10150/195730
Title:
The Role of Metabolism in Ecstasy-Mediated Serotonergic Neurotoxicity
Author:
Erives Quezada, Gladys Vanessa
Issue Date:
2009
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
3,4-(±)-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative commonly used as a recreational drug. Although the selectivity of MDMA for the serotonergic system in rat and humans is well established, the specific mechanism associated with MDMA-induced neurotoxicity is not fully understood. The long-term neurotoxicity of MDMA appears to be dependent upon systemic metabolism since direct administration of MDMA into the brain fails to reproduce the neurotoxic effects seen following peripheral administration, indicating that the parent compound alone is unlikely to be responsible for the neurotoxicity. MDMA is O-demethylenated to the catechol metabolite N-methyl-α-methyldopamine (N-Me-α-MeDA) and N-demethylated to MDA by cytochrome (s) P450 (CYP450). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-α-MeDA and α-MeDA are neurotoxic and can be found in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, we investigated the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA at 12-h intervals for a total of four injections led to a significant accumulation of the N-Me-α-MeDA thioether metabolites in striatal dialysate. In contrast, acute release of 5-HT concentrations was decreased. Since isoenzymes of the CYP2D subfamily (30% metabolism), and the CYP2B or CYP3A1 isoforms, catalyze the low and high KM O-demethylenation reactions, respectively, we subsequently examined the potential role of CYP2D1 in both a genetic and pharmacological model. The data is consistent with the hypothesis that systemic metabolism of MDMA contributes to MDMA-induced serotonergic neurotoxicity via the 20) generation of reactive metabolites. In both the genetic and pharmacological models of CYP2D1 deficiency, attenuation of MDMA-mediated decreases in brain 5-HT concentrations were in the same range (30-40%). Finally, we examined the contribution of various transporters using genetic and pharmacological models to investigate the mechanisms regulating the concentration of thioether metabolites in MDMA neurotoxicity. The data suggest that by regulating various transporters and brain concentrations of the neurotoxic thioether metabolites of MDMA, may subsequently modulate the degree of neurotoxicity. However, further studies are necessary to understand the precise mechanism by which Mrp’s and Oat1 transporters modulate MDMA-neurotoxicity. Taken together, these studies are consistent with the view that neurotoxicity of MDMA requires systemic metabolism to form α-MeDA and N-Me-α- MeDA by CYP2D6. Therefore, It is likely that neurotoxicity is mediated by the formation of systemic neurotoxic metabolites.
Type:
text; Electronic Dissertation
Keywords:
MDMA; metabolism; neurotoxicity; rat; serotonin; thioether metabolites
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology & Toxicology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Monks, Terrence J

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleThe Role of Metabolism in Ecstasy-Mediated Serotonergic Neurotoxicityen_US
dc.creatorErives Quezada, Gladys Vanessaen_US
dc.contributor.authorErives Quezada, Gladys Vanessaen_US
dc.date.issued2009en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstract3,4-(±)-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative commonly used as a recreational drug. Although the selectivity of MDMA for the serotonergic system in rat and humans is well established, the specific mechanism associated with MDMA-induced neurotoxicity is not fully understood. The long-term neurotoxicity of MDMA appears to be dependent upon systemic metabolism since direct administration of MDMA into the brain fails to reproduce the neurotoxic effects seen following peripheral administration, indicating that the parent compound alone is unlikely to be responsible for the neurotoxicity. MDMA is O-demethylenated to the catechol metabolite N-methyl-α-methyldopamine (N-Me-α-MeDA) and N-demethylated to MDA by cytochrome (s) P450 (CYP450). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-α-MeDA and α-MeDA are neurotoxic and can be found in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, we investigated the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA at 12-h intervals for a total of four injections led to a significant accumulation of the N-Me-α-MeDA thioether metabolites in striatal dialysate. In contrast, acute release of 5-HT concentrations was decreased. Since isoenzymes of the CYP2D subfamily (30% metabolism), and the CYP2B or CYP3A1 isoforms, catalyze the low and high KM O-demethylenation reactions, respectively, we subsequently examined the potential role of CYP2D1 in both a genetic and pharmacological model. The data is consistent with the hypothesis that systemic metabolism of MDMA contributes to MDMA-induced serotonergic neurotoxicity via the 20) generation of reactive metabolites. In both the genetic and pharmacological models of CYP2D1 deficiency, attenuation of MDMA-mediated decreases in brain 5-HT concentrations were in the same range (30-40%). Finally, we examined the contribution of various transporters using genetic and pharmacological models to investigate the mechanisms regulating the concentration of thioether metabolites in MDMA neurotoxicity. The data suggest that by regulating various transporters and brain concentrations of the neurotoxic thioether metabolites of MDMA, may subsequently modulate the degree of neurotoxicity. However, further studies are necessary to understand the precise mechanism by which Mrp’s and Oat1 transporters modulate MDMA-neurotoxicity. Taken together, these studies are consistent with the view that neurotoxicity of MDMA requires systemic metabolism to form α-MeDA and N-Me-α- MeDA by CYP2D6. Therefore, It is likely that neurotoxicity is mediated by the formation of systemic neurotoxic metabolites.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectMDMAen_US
dc.subjectmetabolismen_US
dc.subjectneurotoxicityen_US
dc.subjectraten_US
dc.subjectserotoninen_US
dc.subjectthioether metabolitesen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMonks, Terrence Jen_US
dc.contributor.committeememberLau, Serrine Sen_US
dc.contributor.committeememberRegan, John Wen_US
dc.contributor.committeememberLai, Josephineen_US
dc.identifier.proquest10391en_US
dc.identifier.oclc752259940en_US
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