The Role Of Sertonin And Vesicular Monoamine Transporters In The Adverse Responses To Methylenedioxymethamphetamine
type: CreativeWork
description: 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 mai…
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 mai…
author: Lizarraga-Zazueta, Lucina Eridna
language: en_US
keywords: Hyperthermia, MDMA, Neurotoxicity, SERT, VMAT2, Pharmacology & Toxicology, Hyperactivity
date published: 2014
date modified: 2026-07-24T00:57:45Z
provider: University of Arizona
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: The University of Arizona.

PropertyValue
property ID: Handle
value: http://hdl.handle.net/10150/332686