The Neurotoxic Effects of 3,4-Methylenedioxymethamphetamine (MDMA) and Methamphetamine on Serotonin, Dopamine, and GABA-ergic Terminals: An In-Vitro Autoradiographic Study In Rats

doi:10.1016/j.neuro.2004.06.003

NeuroToxicology

Volume 25, Issue 6, December 2004, Pages 905-914

https://doi.org/10.1016/j.neuro.2004.06.003 Get rights and content

Abstract

Damage to serotonin (5-HT) terminals following doses of 3,4-methylenedioxymethamphetamine (MDMA) is well documented, and this toxicity is thought to be related to dopamine release that is potentiated by the 5-HT_2A/2C agonist effects of the drug [Neurotoxicology 19 (3) (1998) 427]. Although MDMA and methamphetamine (METH) have some similar dopaminergic activities, they differ in their 5-HT agonistic properties. It is reasoned that the study of the resultant toxicity following equimolar doses of MDMA and METH on both dopamine and 5-HT terminals should offer a comparison of the ability of these drugs to induce neurotoxicity. In order to measure the toxic effects to the brain, rats were given equimolar doses of MDMA (40 mg/kg/day) and METH (32 mg/kg/day) in subcutaneously implanted osmotic minipumps for a period of 5 days, and in-vitro autoradiography using [ $^{3} H$ ]-paroxetine, [ $^{3} H$ ]-mazindol, [ $^{3} H$ ]-methylspiperone, and [ $^{3} H$ ]-flunitrazepam, was performed on brain sections. The results showed that METH was more toxic to 5-HT terminals than MDMA in forebrain regions, including the anterior cingulate, caudate nucleus, nucleus accumbens, and septum. METH was also more toxic than MDMA to dopamine terminals in the habenula, and posterior retrosplenial cortex. Therefore, we find that METH was more toxic to 5-HT and dopamine terminals in specific brain regions in both pre and post-synaptic sites following continuous equimolar dosing.

Section snippets

INTRODUCTION

The abuse of the popular “rave” drug 3,4-methylenedioxymethamphetamine (MDMA) is at an all time high (Yacoubian et al., 2003) and there is much debate concerning the neurotoxic effects of this phenethylamine. Because the chemical structures and pharmacological properties of MDMA and methamphetamine (METH) share some similarities, a comparison of the drugs neurotoxic abilities can yield further understanding of the danger involved in taking these compounds. Moreover, researching the toxic

METHODS

Female Sprague–Dawley rats bred at UCLA weighing between 212 and 264 g were individually housed, maintained on a reverse 12 h cycle, and had food and water available ad-libitum. Animals were randomly separated into either control (n = 8), MDMA (n = 8), or METH-treated groups (n = 7), were anesthetized with halothane, had Alzet osmotic minipumps (Alza Corp.) model 2mL1 surgically implanted sub-cutaneously, and had the incision closed with wound clips. The minipumps were filled with (±)-MDMA HCl in

[ $^{3} H$ ]-Paroxetine

A two-way RM ANOVA showed that there were significant differences between the drug-treated groups, F(2, 196) = 61.3, P < 0.0001, and brain regions, F(14, 196) = 13.28, P < 0.0001, and that there was a significant interaction between them, F(28, 196) = 3.43, P < 0.0001. All brain regions with the exception of the median raphe showed significantly different amounts of binding between the drug-treated, and control groups (see Fig. 1). There were differing amounts of binding in the median raphe

DISCUSSION

The METH-treated animals appeared to have more damage to presynaptic 5-HT terminals in the frontal area of the brain than the MDMA-treated animals, as evidenced by decreased [ $^{3} H$ ]-paroxetine binding. It has been shown that MDMA damages the fine axons emanating from the dorsal, but not the large thicker beaded axons emanating from the median raphe, which may account for the differences seen here (Callahan et al., 2001, Molliver et al., 1990). It may be that the sites measured in the rostral

CONCLUSIONS

The vast majority of studies on MDMA have shown degeneration in the neocortex, striatum, and hippocampus (Commins et al., 1986, O’Hearn et al., 1988). These areas, as well as a multitude of other brain regions, were examined in a systematic rostral to caudal fashion in MDMA and METH-treated animals. It was found that forebrain areas including the anterior cingulate, caudate, nucleus accumbens, and hippocampus may be more susceptible to the toxic effects of these drugs. Moreover, METH treatment

Acknowledgements

We would like to thank Dr. Gaylord Ellison for his generosity in support of this study. Research sponsored by NIDA Grant DA 07344.

All experiments performed in concordance with The University of California at Los Angeles Animal Research Committee.

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The Neurotoxic Effects of 3,4-Methylenedioxymethamphetamine (MDMA) and Methamphetamine on Serotonin, Dopamine, and GABA-ergic Terminals: An In-Vitro Autoradiographic Study In Rats

Abstract

Section snippets

INTRODUCTION

METHODS

[3H]-Paroxetine

DISCUSSION

CONCLUSIONS

Acknowledgements

Pharm Biochem Behav

Eur J Neuropsychopharm

Brain Res

Brain Res

Lancet

Brain Res

Brain Res

Eur. J. Pharm

Brain Res

Biochem Pharmacol

3,4-Methylenedioxymethamphetamine destroys serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]-paroxetine-labeled serotonin uptake sites

J Pharm Exp Ther

Long-term impairment of anterograde axonal transport along fiber projections originating in the rostral raphe nuclei after treatment with fenfluramine or methylenedioxymethamphetamine

Synapse

Stereochemical differences in the metabolism of MDMA in vivo and in vitro: a pharmakokinetic analysis

Drug Metabol Dispos

Relevance of pharmacokinetic parameters in animal models of methamphetamine abuse

Synapse

The hyperthermic and neurotoxic effects of MDMA and MDA in the dark agouti rat: a model of the CYP2D6 poor metabolizers phenotype

Br. J Pharm

Biochemical and histological evidence that methylenedioxymethamphetamine (MDMA) is toxic to neurons in the rat brain

J Pharm Exp Ther

An appraisal of the pharmacological and toxicological effects of a single oral administration of 3,4-methylenedioxymethamphetamine (MDMA) in the rat

Pharm Toxicol

Long-term changes in brain following continuous phencyclidine administration: an autoradiographic study using flunitrazepam, ketanserin, mazindol, quinuclidinyl benzilate, piperidyl-3,4-3H (N)-TCP, and AMPA receptor ligands

Pharmacol Toxicol

Dimorphic features of the different (-containing GABA-A receptor subtypes in the cortico-basal ganglia system of two distantly related mammals (hedgehog and rat)

Exp Brain Res

Neuropharmacology and neurotoxicity of 3,4-methylenedioxymethamphetamine

Methods Mol Med

[ $^{3} H$ ]-Paroxetine