Molecular Neurobiology

, Volume 39, Issue 3, pp 210–271

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

  • João Paulo Capela
  • Helena Carmo
  • Fernando Remião
  • Maria Lourdes Bastos
  • Andreas Meisel
  • Félix Carvalho
Article

DOI: 10.1007/s12035-009-8064-1

Cite this article as:
Capela, J.P., Carmo, H., Remião, F. et al. Mol Neurobiol (2009) 39: 210. doi:10.1007/s12035-009-8064-1

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.

Keywords

Ecstasy MDMA Drug abuse Hallucinogen Neurotoxicity Mechanism of neurodegeneration 

Abbreviations

Amph

Amphetamine

AMPT

α-Methyl-p-tyrosine

ATP

Adenosine triphosphate

AUC

Area under the curve

Cmax

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

Ke

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

t1/2

Elimination half-life

Tmax

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

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • João Paulo Capela
    • 1
    • 2
  • Helena Carmo
    • 1
  • Fernando Remião
    • 1
  • Maria Lourdes Bastos
    • 1
  • Andreas Meisel
    • 3
  • Félix Carvalho
    • 1
  1. 1.REQUIMTE (Rede de Química e Tecnologia), Toxicology Department, Faculty of PharmacyUniversity of PortoPortoPortugal
  2. 2.Faculty of Health SciencesUniversity Fernando PessoaPortoPortugal
  3. 3.Department of Experimental Neurology and Center for Stroke ResearchCharité-UniversitätsmedizinBerlinGermany