MDMA-induced neurotoxicity: Parameters of degeneration and recovery of brain serotonin neurons

doi:10.1016/0091-3057(88)90155-4

Pharmacology Biochemistry and Behavior

Volume 29, Issue 2, February 1988, Pages 269-274

https://doi.org/10.1016/0091-3057(88)90155-4 Get rights and content

Abstract

This study investigates a number of parameters that influence the neurotoxic effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin (5-HT) neurons in brain. Both the dose and number of injections of MDMA affect the degree of neurotoxicity on 5-HT axons and terminals as assessed by decreases in the content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) and the density of 5-HT uptake sites. Repeated systemic administration of various doses of MDMA (5–20 mg/kg twice daily for 4 consecutive days) results in dose-dependent decreases in 5-HT, 5-HIAA and 5-HT uptake sites. Increasing the number of injections of MDMA resulted in progressively greater reductions in 5-HT and 5-HIAA which occurred prior to decreases in 5-HT uptake sites. In contrast, no significant changes were observed in the density of norepinephrine uptake sites following single or repeated injections of 20 mg/kg MDMA. With respect to neuronal regeneration, following an initial 90% loss of 5-HT uptake sites after treatment with MDMA, the recovery of these sites occurred over a protracted period of time; a marked 25% reduction was seen at 6 months and the concentration of 5-HT uptake sites returned to control levels at 12 months following treatment with MDMA. Pretreatment with the selective 5-HT uptake blocker, citalopram, prior to each injection of MDMA prevented the neurotoxic effects of MDMA on the 5-HT parameters described above suggesting that active uptake of MDMA or a MDMA-related substance into brain 5-HT neurons was involved in the neurotoxic actions of the drug. In addition, the neurodegenerative effects of MDMA on 5-HT neurons exhibited some species specificity as comparable decreases in cerebral cortical 5-HT, 5-HIAA and 5-HT uptake sites were observed in rat and guinea pig while no significant changes in any of these serotonergic parameters were seen in mouse brain.

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Citation Excerpt :
It should also be mentioned that although all animals had been self-administering cocaine and MDMA, the number of injection during MDMA self-administration session were lower than during cocaine self-administration session. Significant different between cocaine and MDMA came from: (1) alternative mechanism of action to increase the level monoamines from their respective axon terminals (see Introduction [10–17]); (2) both drugs cause long-lasting suppression of dopamine and 5-HT neurons, although MDMA alters twice more on 5-HT neurons than on dopamine [5,13], (3) MDMA requires much longer time (few minutes), as compared to cocaine (few seconds) to initiate suppression of 5-HT and dopamine neuron activity, but the effect of suppression can be prolonged till 6 h, while in cocaine till 2 h [33]. Weaker responses MDMA on dopamine neurons, associated with drug-induced reinforcing property, produces much weaker drug dependence than cocaine (long time of acquisition, a larger percentage of non-dependent animals [present data, 5,24,25]), while stronger responses on 5-HT neurons, associated with drug-induced euphoria property, produces strong but extended effect correlated with amount of drug necessary to induces the effect (the number of injection during self-administration session, [present data, 5,24,25]).
Several studies strongly support the role of the dopamine D₂-like and glutamate mGlu₅ receptors in psychostimulant reward and relapse.
The present study employed cocaine or MDMA self-administration with yoked-triad procedure in rats to explore whether extinction training affects the drug-seeking behavior and the D₂-like and mGlu₅ receptor B_max and K_d values in several regions of the animal brain.
Both cocaine and MDMA rats developed maintenance of self-administration, but MDMA evoked lower response rates and speed of self-administration acquisition. During reinstatement tests, cocaine or MDMA seeking behavior was produced by either exposure to the drug-associated cues or drug-priming injections. The extinction training after cocaine self-administration did not alter significantly D₂-like receptor expression the in the limbic and subcortical brain areas, while MDMA yoked rats showed a decrease of the D_2-like binding density in the nucleus accumbens and increase in the hippocampus and a rise of affinity in the striatum and hippocampus. Interestingly, in the prefrontal cortex a reduction in the mGlu₅ receptor density in cocaine- or MDMA-abstinent rats was demonstrated, with significant effects being observed after previous MDMA exposure. Moreover, rats self-administered cocaine showed a rise in the density of mGlu₅ receptor for the nucleus accumbens.
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Using in vivo microdialysis, a comparative study was conducted to examine the effects of amphetamine-related compounds (methamphetamine, MAP; 3,4-methylenedioxymethamphetamine, MDMA; p-methoxyamphetamine, PMA; p-methoxymethamphetamine, PMMA; 4-methylthioamphetamine, 4-MTA; 3,4,5-trimethoxyamphetamine, TMA; 2,5-dimethoxy-4-iodoamphetamine, DOI) on extracellular levels of serotonin (5-HT) and dopamine (DA). Dialysates were assayed using HPLC equipped with electrochemical detector following i.p. administration with each drug at a dose of 5 mg/kg. MAP was found to drastically and rapidly increase 5-HT and DA levels (870% and 1460%, respectively). PMA, PMMA, and 4-MTA slightly increased DA levels (150–290%) but remarkably increased 5-HT levels (540–900%). In contrast, TMA and DOI caused no detectable changes in levels of both monoamines. We observed that the potent DA-releasing action of MAP was remarkably decreased by introduction of methoxy or methylthio group at the para position (MAP vs. PMMA or 4-MTA), but introduction of two additional adjacent methoxy groups into PMA totally abolished its 5-HT-/DA-releasing action (PMA vs. TMA). In addition, para-mono-substituted compounds inhibited both monoamine oxidase (MAO) enzymes more strongly than other compounds; PMA and 4-MTA exhibited submicromolar IC₅₀ values for MAO-A. On the other hand, TMA scarcely affected the activity of both MAO enzymes as well as extracellular levels of 5-HT and DA. In this comparative study, MDMA, PMA, and 4-MTA functioned similar to PMMA, a typical empathogen; these findings therefore could be helpful in clarifying the psychopharmacological properties of amphetamine-related, empathogenic designer drugs.

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MDMA-induced neurotoxicity: Parameters of degeneration and recovery of brain serotonin neurons

Abstract

Drug Alcohol Depend

Brain Res

Brain Res

Eur J Pharmacol

Eur J Pharmacol

J Biol Chem

Eur J Pharmacol

Biochem Pharmacol

Eur J Pharmacol

Eur J Pharmacol

Getting high on “Ecstacy”

Newsweek

3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: Quantification of neurodegeneration by measurement of 3H-paroxetine-labeled serotonin uptake sites

J Pharmacol Exp Ther

MDMA-induced neurotoxicity visualized by in vitro autoradiography: Differential sensitivity of serotonergic neurons

The metabolism of amphetamines and related stimulants in animals and man

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

J Pharmacol Exp Ther

Neurochemical effects of serotonin neurotoxins: An introduction

Ann NY Acad Sci

3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: Quantification of neurodegeneration by measurement of ³H-paroxetine-labeled serotonin uptake sites