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Methamphetamine and MDMA Neurotoxicity: Biochemical and Molecular Mechanisms

  • Verónica Bisagno
  • Jean Lud CadetEmail author
Reference work entry

Abstract

Methamphetamine (METH) and its analogs, methylenedioxymethamphetamine (MDMA), are psychostimulant drugs with high abuse liability. The two drugs are also very neurotoxic. In the case of METH, the behavioral and neurotoxic effects of the drug occur because it alters dopamine terminal physiology and causes massive release of dopamine (DA) in the synaptic cleft in brain regions that receive dopaminergic projections from the midbrain. The increase of synaptic DA is compounded by the ability of METH to block DA reuptake into DA terminals. METH toxicity is not only accompanied by terminal dysfunction but also by causing dysfunction of complex networks that subserve cognitive and emotional processes. MDMA is a ring-substituted derivative of phenylisopropylamine which is structurally similar to METH. MDMA is a substrate of the serotonin transporter (SERT) via which it enters monoaminergic neurons and causes release of serotonin (5-HT) from storage vesicles. This is followed by 5-HT release into the synaptic cleft by reversal of normal SERT function. MDMA is selectively neurotoxic to serotonergic nerve terminals in rats, guinea pigs, and nonhuman primates. MDMA users consistently show reduced SERT radionuclide ligand binding across multiple brain regions. There is also evidence that MDMA users can suffer from cognitive deficits. However, the relation of DA and/or 5-HT depletion to cognitive impairments remains to be clarified in METH and MDMA users. Results from these studies are likely to impact the therapeutic approaches to the treatment of patients who suffer from METH and MDMA addiction.

Keywords

Tyrosine Hydroxylase Mdma User Incentive Salience MDMA Administration SERT Binding 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

List of Abbreviations

5-HIAA

5-hydroxyindoleacetic acid

5-HT

Serotonin

α-MT

α-methyl-p-tyrosine

CNS

Central nervous system

COMT

Catechol-O-methyltransferase

CuZnSOD

Copper–zinc superoxide dismutase

DA

Dopamine

DAT

Dopamine transporter

ER-

Endoplasmic reticulum-

HHA

3,4-Dihydroxyamphetamine

HHMA

3,4-Dihydroxymethamphetamine

HMA

4-Hydroxy-3-methoxy-amphetamine

L-DOPA

L-3,4-Dihydroxyphenylalanine

MDA

Methylenedioxyamphetamine

MDMA

Methylenedioxymethamphetamine

METH

Methamphetamine

MK-801

Dizocilpine

MTF-1

Metal-responsive transcription factor 1

MTs

Metallothioneins

NET

Norepinephrine transporter

Nrf2

NF-E2-Related factor 2

PARP

Poly(ADP-ribose) polymerase

ROS

Reactive oxygen species

SERT

Serotonin transporter

TH

Tyrosine hydroxylase

TPH

Tryptophan hydroxylase

VMAT2

Vesicular monoamine transporter 2

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET)Buenos AiresArgentina
  2. 2.NIDA Intramural Program, Molecular Neuropsychiatry Research BranchNIDA/NIH/DHHSBaltimoreUSA

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