Show simple item record

dc.contributor.advisorMonks, Terrence J.en_US
dc.contributor.authorHerndon, Joseph Menzel
dc.creatorHerndon, Joseph Menzelen_US
dc.date.accessioned2013-12-16T23:03:53Z
dc.date.available2013-12-16T23:03:53Z
dc.date.issued2013
dc.identifier.urihttp://hdl.handle.net/10150/306920
dc.description.abstract3,4-(±)-Methylenedioxymethamphetamine (MDMA, ecstasy) is a widely abused amphetamine derivative. The metabolism of MDMA is thought to be a necessary component of MDMA-induced neurotoxicity, as direct administration of MDMA into the central nervous system of rats failed to reproduce the hallmark serotonin deficits seen following systemic administration of MDMA. Mechanistic questions remain regarding how MDMA elicits this neurotoxicity. Work of this thesis was undertaken to examine how MDMA-induced neurotoxicity is affected by the activity of two polymorphic enzymes involved in the metabolism of MDMA, namely cytochrome P450 family member 2D6 (CYP2D6) and catechol-O-methyltransferase (COMT), as well as the potential role microglia play in the facilitation of this neurotoxicity. Inhibition of CYP2D1, the homolog of human CYP2D6 in the rat, resulted in an attenuation of serotonergic neurotoxicity following MDMA-administration. In both a pharmacological model and a genetic model of CYP2D1 inhibition, serotonin deficits were alleviated when compared to normal-activity CYP2D1 counterparts. Inhibition of COMT, the primary detoxication enzyme in the MDMA pathway, resulted in potentiation of MDMA-induced neurotoxicity. In a pharmacological model of COMT inhibition, rats displayed greater long-term serotonin deficits after COMT inhibition. Mice devoid of COMT proved sensitive to the lethal hyperthermic effects of MDMA, illustrating the importance of this enzyme in preventing the acute toxicity of MDMA. Brain lesions often elicit a microglial response. Microglia have the potential of both beneficial and deleterious actions in the brain. Whether microglia are activated by nerve terminal degeneration produced by MDMA is an area of ongoing debate. Systemically delivered MDMA produces a modest increase in the amount of microglial cells present in the parietal cortex of rats over a one-week period. MDMA also increased the phagocytic activity of microglia in the cortex. The studies described herein support the hypothesis that metabolism is critical in MDMA-induced neurotoxicity. Furthermore, as both CYP2D6 and COMT are polymorphic in the human population, certain individuals are more at risk for severe serotonergic toxicity following MDMA administration. Finally, while microglia are likely not the cause of MDMA-induced neurotoxicity, contributions of these cells cannot be dismissed.
dc.language.isoen_USen_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.subjectCYP2D6en_US
dc.subjectMDMAen_US
dc.subjectMicrogliaen_US
dc.subjectNeurotoxicityen_US
dc.subjectPharmacology & Toxicologyen_US
dc.subjectCOMTen_US
dc.titleMethylenedioxymethamphetamine-Induced Neurotoxicity: The Role of Hepatic Enzymes Cytochrome P450 2D6 and Catechol-O-Methyltransferase and Contribution of Microgliaen_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.contributor.committeememberMonks, Terrence J.en_US
dc.contributor.committeememberLau, Serrine S.en_US
dc.contributor.committeememberLai, Josephine Y.en_US
dc.contributor.committeememberWright, Stephen H.en_US
dc.contributor.committeememberCherrington, Nathan J.en_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.namePh.D.en_US
refterms.dateFOA2018-06-25T05:46:54Z
html.description.abstract3,4-(±)-Methylenedioxymethamphetamine (MDMA, ecstasy) is a widely abused amphetamine derivative. The metabolism of MDMA is thought to be a necessary component of MDMA-induced neurotoxicity, as direct administration of MDMA into the central nervous system of rats failed to reproduce the hallmark serotonin deficits seen following systemic administration of MDMA. Mechanistic questions remain regarding how MDMA elicits this neurotoxicity. Work of this thesis was undertaken to examine how MDMA-induced neurotoxicity is affected by the activity of two polymorphic enzymes involved in the metabolism of MDMA, namely cytochrome P450 family member 2D6 (CYP2D6) and catechol-O-methyltransferase (COMT), as well as the potential role microglia play in the facilitation of this neurotoxicity. Inhibition of CYP2D1, the homolog of human CYP2D6 in the rat, resulted in an attenuation of serotonergic neurotoxicity following MDMA-administration. In both a pharmacological model and a genetic model of CYP2D1 inhibition, serotonin deficits were alleviated when compared to normal-activity CYP2D1 counterparts. Inhibition of COMT, the primary detoxication enzyme in the MDMA pathway, resulted in potentiation of MDMA-induced neurotoxicity. In a pharmacological model of COMT inhibition, rats displayed greater long-term serotonin deficits after COMT inhibition. Mice devoid of COMT proved sensitive to the lethal hyperthermic effects of MDMA, illustrating the importance of this enzyme in preventing the acute toxicity of MDMA. Brain lesions often elicit a microglial response. Microglia have the potential of both beneficial and deleterious actions in the brain. Whether microglia are activated by nerve terminal degeneration produced by MDMA is an area of ongoing debate. Systemically delivered MDMA produces a modest increase in the amount of microglial cells present in the parietal cortex of rats over a one-week period. MDMA also increased the phagocytic activity of microglia in the cortex. The studies described herein support the hypothesis that metabolism is critical in MDMA-induced neurotoxicity. Furthermore, as both CYP2D6 and COMT are polymorphic in the human population, certain individuals are more at risk for severe serotonergic toxicity following MDMA administration. Finally, while microglia are likely not the cause of MDMA-induced neurotoxicity, contributions of these cells cannot be dismissed.


Files in this item

Thumbnail
Name:
azu_etd_13000_sip1_m.pdf
Size:
7.951Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record