The Role Of Sertonin And Vesicular Monoamine Transporters In The Adverse Responses To Methylenedioxymethamphetamine

Persistent Link:
http://hdl.handle.net/10150/332686
Title:
The Role Of Sertonin And Vesicular Monoamine Transporters In The Adverse Responses To Methylenedioxymethamphetamine
Author:
Lizarraga-Zazueta, Lucina Eridna
Issue Date:
2014
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, Ecstasy) is a widely abused amphetamine derivative with potent stimulant properties. The neuropharmacological effects of MDMA are biphasic in nature. MDMA initially causes synaptic monoamine release, primarily of serotonin (5-HT), producing hyperthermia and hyperactivity (5-HT syndrome). Conversely, the long-term effects of MDMA manifest as a prolonged depletion in 5-HT, and structural damage to serotonergic nerve terminals. Monoamine transporter systems at the plasma membrane and storage vesicles of 5-HT neurons have been implicated in MDMA toxicity. Nonetheless, many mechanistic questions remain regarding the precise role of uptake transporters in MDMA neurotoxicity. The present study was designed to address the importance of the serotonin reuptake transporter (SERT) and the vesicular monoamine transporter 2 (VMAT2) to the physiological, behavioral and neurotoxic responses to MDMA. SERT functions as a primary regulator of 5-HT homeostasis, mediating the reuptake of 5-HT from the synaptic space following its release during neurotransmission. SERT is a molecular target site for MDMA and many antidepressant agents such as the selective serotonin reuptake inhibitor (SSRI) class. Pharmacological inhibition of SERT protects against MDMA-induced serotonergic neurotoxicity. Thus, the effects of MDMA are in part mediated by an ability to interact with and inhibit SERT. Using a SERT-knockout (SERT-KO) rat model, we determined that SERT deficiency modulated the acute toxicities of MDMA, such as hyperthermia and hyperactivity, whilst completely preventing long-term depletions in tissue 5-HT levels, indicating the abolishment of neurotoxicity. Disruption of vesicular monoamine storage via interaction with VMAT2 has also been implicated in MDMA neurotoxicity. VMAT2 participates in the transport of monoamine neurotransmitters, in particular 5-HT and dopamine (DA), into intra-neuronal storage vesicles. As such, VMAT2 is critical in maintaining neuronal health by preventing neurotransmitter oxidation within the cytosol. Pharmacological inhibition of VMAT2 with Ro4-1284 reduced MDMA-induced hyperactivity and averted hyperthermia along with persistent serotonergic deficits. Overall, our results corroborate the hypothesis that SERT and VMAT2 are critical to the in vivo effects of MDMA. Furthermore, given that VMAT2 inhibition diminished the behavioral response to MDMA in rats, pharmacological manipulation of this transporter could be used in the treatment of MDMA abuse and overdose.
Type:
text; Electronic Dissertation
Keywords:
Hyperthermia; MDMA; Neurotoxicity; SERT; VMAT2; Pharmacology & Toxicology; Hyperactivity
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology & Toxicology
Degree Grantor:
University of Arizona
Advisor:
Monks, Terrence J.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen
dc.titleThe Role Of Sertonin And Vesicular Monoamine Transporters In The Adverse Responses To Methylenedioxymethamphetamineen_US
dc.creatorLizarraga-Zazueta, Lucina Eridnaen_US
dc.contributor.authorLizarraga-Zazueta, Lucina Eridnaen_US
dc.date.issued2014-
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, Ecstasy) is a widely abused amphetamine derivative with potent stimulant properties. The neuropharmacological effects of MDMA are biphasic in nature. MDMA initially causes synaptic monoamine release, primarily of serotonin (5-HT), producing hyperthermia and hyperactivity (5-HT syndrome). Conversely, the long-term effects of MDMA manifest as a prolonged depletion in 5-HT, and structural damage to serotonergic nerve terminals. Monoamine transporter systems at the plasma membrane and storage vesicles of 5-HT neurons have been implicated in MDMA toxicity. Nonetheless, many mechanistic questions remain regarding the precise role of uptake transporters in MDMA neurotoxicity. The present study was designed to address the importance of the serotonin reuptake transporter (SERT) and the vesicular monoamine transporter 2 (VMAT2) to the physiological, behavioral and neurotoxic responses to MDMA. SERT functions as a primary regulator of 5-HT homeostasis, mediating the reuptake of 5-HT from the synaptic space following its release during neurotransmission. SERT is a molecular target site for MDMA and many antidepressant agents such as the selective serotonin reuptake inhibitor (SSRI) class. Pharmacological inhibition of SERT protects against MDMA-induced serotonergic neurotoxicity. Thus, the effects of MDMA are in part mediated by an ability to interact with and inhibit SERT. Using a SERT-knockout (SERT-KO) rat model, we determined that SERT deficiency modulated the acute toxicities of MDMA, such as hyperthermia and hyperactivity, whilst completely preventing long-term depletions in tissue 5-HT levels, indicating the abolishment of neurotoxicity. Disruption of vesicular monoamine storage via interaction with VMAT2 has also been implicated in MDMA neurotoxicity. VMAT2 participates in the transport of monoamine neurotransmitters, in particular 5-HT and dopamine (DA), into intra-neuronal storage vesicles. As such, VMAT2 is critical in maintaining neuronal health by preventing neurotransmitter oxidation within the cytosol. Pharmacological inhibition of VMAT2 with Ro4-1284 reduced MDMA-induced hyperactivity and averted hyperthermia along with persistent serotonergic deficits. Overall, our results corroborate the hypothesis that SERT and VMAT2 are critical to the in vivo effects of MDMA. Furthermore, given that VMAT2 inhibition diminished the behavioral response to MDMA in rats, pharmacological manipulation of this transporter could be used in the treatment of MDMA abuse and overdose.en_US
dc.typetexten
dc.typeElectronic Dissertationen
dc.subjectHyperthermiaen_US
dc.subjectMDMAen_US
dc.subjectNeurotoxicityen_US
dc.subjectSERTen_US
dc.subjectVMAT2en_US
dc.subjectPharmacology & Toxicologyen_US
dc.subjectHyperactivityen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMonks, Terrence J.en_US
dc.contributor.committeememberMonks, Terrence J.en_US
dc.contributor.committeememberRegan, John W.en_US
dc.contributor.committeememberLau, Serrine S.en_US
dc.contributor.committeememberLai, Josephineen_US
dc.contributor.committeememberWright, Stephenen_US
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