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Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview

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Abstract

“Ecstasy” [(±)-3,4-methylenedioxymethamphetamine, MDMA, XTC, X, E] is a psychoactive recreational hallucinogenic substance and a major worldwide drug of abuse. Several reports raised the concern that MDMA has the ability to induce neurotoxic effects both in laboratory animals and humans. Despite more than two decades of research, the mechanisms by which MDMA is neurotoxic are still to be fully elucidated. MDMA induces serotonergic terminal loss in rats and also in some mice strains, but also a broader neuronal degeneration throughout several brain areas such as the cortex, hippocampus, and striatum. Meanwhile, in human “ecstasy” abusers, there are evidences for deficits in seronergic biochemical markers, which correlate with long-term impairments in memory and learning. There are several factors that contribute to MDMA-induced neurotoxicity, namely, hyperthermia, monoamine oxidase metabolism of dopamine and serotonin, dopamine oxidation, the serotonin transporter action, nitric oxide, and the formation of peroxinitrite, glutamate excitotoxicity, serotonin 2A receptor agonism, and, importantly, the formation of MDMA neurotoxic metabolites. The present review covered the following topics: history and epidemiology, pharmacological mechanisms, metabolic pathways and the influence of isoenzyme genetic polymorphisms, as well as the acute effects of MDMA in laboratory animals and humans, with a special focus on MDMA-induced neurotoxic effects at the cellular and molecular level. The main aim of this review was to contribute to the understanding of the cellular and molecular mechanisms involved in MDMA neurotoxicity, which can help in the development of therapeutic approaches to prevent or treat the long-term neuropsychiatric complications of MDMA abuse in humans.

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Abbreviations

Amph:

Amphetamine

AMPT:

α-Methyl-p-tyrosine

ATP:

Adenosine triphosphate

AUC:

Area under the curve

C max :

Maximum concentration

CNS:

Central nervous system

COMT:

Catechol-O-methyltransferase

CSF:

Cerebrospinal fluid

CTX:

Cortex

CYP:

Cytochrome P450

DA:

Dopamine

DAT:

Dopamine transporter

DHT:

Dihydroxytriptamine

DOI:

(±)-2,5-Dimethoxy-4-iodoamphetamine

EC50 :

Effective concentration 50%

EU:

European Union

GABA:

Gamma-aminobutyric acid

GFAP:

Glial fibrillary acidic protein

GLU:

Glutamate

GSH:

Glutathione

GST:

Glutathione S-transferase

γ-GT:

gamma-glutamyl transpeptidase or gamma-glutamyltransferase

5-HIAA:

5-Hydroxyindoleacetic acid

HIP:

Hippocampus

HMA:

4-Hydroxy-3-methoxyamphetamine, 3-O-Me-α-MeDA

HMMA:

4-Hydroxy-3-methoxymethamphetamine, 3-O-Me-N-Me-α-MeDA

HO :

Hydroxyl radical

H2O2 :

Hydrogen peroxide

5-HT:

5-Hydroxytriptamine, serotonin

5-HTT:

Serotonin transporter

HVA:

4-Hydroxy-3-methoxyphenylacetic acid, homovanillic acid

i.p.:

Intraperitoneal

i.v.:

Intravenous

iCa2+ :

Intracellular calcium

ICV:

Intracerebroventricular

K e :

Elimination constant

KO:

Knockout

MAO:

Monoamine oxidase

MDA:

(±)-3,4-Methylenedioxyamphetamine

MDMA:

(±)-3,4-Methylenedioxymethamphetamine, “ecstasy”

α-MeDA:

α-Methyldopamine, 3,4-Dihydroxyamphetamine, HHA

N-Me-α-MeDA:

N-methyl-α-methyldopamine, 3,4-Dihydroxymethamphetamine, HHMA

Meth:

Methamphetamine

MK-801:

Dizocilpine

NAC:

N-acetylcysteine

NE:

Norepinephrine

NET:

Norepinephrine transporter

NMDA:

N-methyl-d-aspartic acid

l-NAME:

\(N_\omega \)-nitro-l-arginine methyl ester

l-NNA:

\(N_\omega \)-nitro-l-arginine

NO:

Nitric oxide

NO :

Nitric oxide radical

O2 ●− :

Superoxide anion

ONOO :

Peroxynitrite

p.o.:

Per os

PBN:

α-Phenyl-N-tert-butyl nitrone

PND:

Postnatal day

PET:

Positron emission tomography

PKC:

Protein kinase C

R-96544:

(2R,4R)-5-[2-[2-[2-(3-Methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol hydrochloride

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

s.c.:

Subcutaneous

–SH:

Sulfhydryl

SPECT:

Single photon emission computed tomography

SULT:

Sulfotransferase

t 1/2 :

Elimination half-life

T max :

Median time to maximum concentration

T-4,5-D:

Tryptamine-4,5-dione

TPH:

Tryptophan hydroxylase

UGT:

UDP-glucuronosyltransferase

VMAT:

Vesicular monoamine transporter

WT:

Wild type

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