Further studies on the role of metabolites in (±)-3,4- methylenedioxymethamphetamine-induced serotonergic neurotoxicity

Melanie Mueller, Jie Yuan, Anne Felim, Anne Neudörffer, Frank T. Peters, Hans H. Maurer, Una D McCann, Martine Largeron, George Ricaurte

Research output: Contribution to journalArticle

Abstract

The mechanism by which the recreational drug (±)-3,4- methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals. We also further evaluated the neurotoxic potential of 5-(N-acetylcystein-S-yl)-HHMA (5-NAC-HHMA), an MDMA metabolite recently implicated in 5-HT neurotoxicity. Lasting serotonergic deficits correlated strongly with pharmacokinetic parameters of MDMA (Cmax and area under the concentration-time curve), more weakly with those of MDA, and not at all with those of HHMA or HMMA (total amounts of the free analytes obtained after conjugate cleavage). HHMA and HMMA could not be detected in the brains of animals with high brain MDMA concentrations and high plasma HHMA and HMMA concentrations, suggesting that HHMA and HMMA do not readily penetrate the blood-brain barrier (either in their free form or as sulfate or glucuronic conjugates) and that little or no MDMA is metabolized to HHMA or HMMA in the brain. Repeated intraparenchymal administration of 5-NAC-HHMA did not produce significant lasting serotonergic deficits in the rat brain. Taken together, these results indicate that MDMA and, possibly, MDA are more important determinants of brain 5-HT neurotoxicity in the rat than HHMA and HMMA and bring into question the role of metabolites (including 5-NAC-HHMA) in MDMA neurotoxicity.

Original languageEnglish (US)
Pages (from-to)2079-2086
Number of pages8
JournalDrug Metabolism and Disposition
Volume37
Issue number10
DOIs
StatePublished - Oct 2009

Fingerprint

N-Methyl-3,4-methylenedioxyamphetamine
Serotonin
Brain
3,4-Methylenedioxyamphetamine
Pharmacokinetics
Presynaptic Terminals
Street Drugs
4-hydroxy-3-methoxymethamphetamine
Blood-Brain Barrier
Sulfates

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Further studies on the role of metabolites in (±)-3,4- methylenedioxymethamphetamine-induced serotonergic neurotoxicity. / Mueller, Melanie; Yuan, Jie; Felim, Anne; Neudörffer, Anne; Peters, Frank T.; Maurer, Hans H.; McCann, Una D; Largeron, Martine; Ricaurte, George.

In: Drug Metabolism and Disposition, Vol. 37, No. 10, 10.2009, p. 2079-2086.

Research output: Contribution to journalArticle

Mueller, Melanie ; Yuan, Jie ; Felim, Anne ; Neudörffer, Anne ; Peters, Frank T. ; Maurer, Hans H. ; McCann, Una D ; Largeron, Martine ; Ricaurte, George. / Further studies on the role of metabolites in (±)-3,4- methylenedioxymethamphetamine-induced serotonergic neurotoxicity. In: Drug Metabolism and Disposition. 2009 ; Vol. 37, No. 10. pp. 2079-2086.
@article{9f6a42935e78453e8db1c10ae1b60bc0,
title = "Further studies on the role of metabolites in (±)-3,4- methylenedioxymethamphetamine-induced serotonergic neurotoxicity",
abstract = "The mechanism by which the recreational drug (±)-3,4- methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals. We also further evaluated the neurotoxic potential of 5-(N-acetylcystein-S-yl)-HHMA (5-NAC-HHMA), an MDMA metabolite recently implicated in 5-HT neurotoxicity. Lasting serotonergic deficits correlated strongly with pharmacokinetic parameters of MDMA (Cmax and area under the concentration-time curve), more weakly with those of MDA, and not at all with those of HHMA or HMMA (total amounts of the free analytes obtained after conjugate cleavage). HHMA and HMMA could not be detected in the brains of animals with high brain MDMA concentrations and high plasma HHMA and HMMA concentrations, suggesting that HHMA and HMMA do not readily penetrate the blood-brain barrier (either in their free form or as sulfate or glucuronic conjugates) and that little or no MDMA is metabolized to HHMA or HMMA in the brain. Repeated intraparenchymal administration of 5-NAC-HHMA did not produce significant lasting serotonergic deficits in the rat brain. Taken together, these results indicate that MDMA and, possibly, MDA are more important determinants of brain 5-HT neurotoxicity in the rat than HHMA and HMMA and bring into question the role of metabolites (including 5-NAC-HHMA) in MDMA neurotoxicity.",
author = "Melanie Mueller and Jie Yuan and Anne Felim and Anne Neud{\"o}rffer and Peters, {Frank T.} and Maurer, {Hans H.} and McCann, {Una D} and Martine Largeron and George Ricaurte",
year = "2009",
month = "10",
doi = "10.1124/dmd.109.028340",
language = "English (US)",
volume = "37",
pages = "2079--2086",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "10",

}

TY - JOUR

T1 - Further studies on the role of metabolites in (±)-3,4- methylenedioxymethamphetamine-induced serotonergic neurotoxicity

AU - Mueller, Melanie

AU - Yuan, Jie

AU - Felim, Anne

AU - Neudörffer, Anne

AU - Peters, Frank T.

AU - Maurer, Hans H.

AU - McCann, Una D

AU - Largeron, Martine

AU - Ricaurte, George

PY - 2009/10

Y1 - 2009/10

N2 - The mechanism by which the recreational drug (±)-3,4- methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals. We also further evaluated the neurotoxic potential of 5-(N-acetylcystein-S-yl)-HHMA (5-NAC-HHMA), an MDMA metabolite recently implicated in 5-HT neurotoxicity. Lasting serotonergic deficits correlated strongly with pharmacokinetic parameters of MDMA (Cmax and area under the concentration-time curve), more weakly with those of MDA, and not at all with those of HHMA or HMMA (total amounts of the free analytes obtained after conjugate cleavage). HHMA and HMMA could not be detected in the brains of animals with high brain MDMA concentrations and high plasma HHMA and HMMA concentrations, suggesting that HHMA and HMMA do not readily penetrate the blood-brain barrier (either in their free form or as sulfate or glucuronic conjugates) and that little or no MDMA is metabolized to HHMA or HMMA in the brain. Repeated intraparenchymal administration of 5-NAC-HHMA did not produce significant lasting serotonergic deficits in the rat brain. Taken together, these results indicate that MDMA and, possibly, MDA are more important determinants of brain 5-HT neurotoxicity in the rat than HHMA and HMMA and bring into question the role of metabolites (including 5-NAC-HHMA) in MDMA neurotoxicity.

AB - The mechanism by which the recreational drug (±)-3,4- methylenedioxymethamphetamine (MDMA) destroys brain serotonin (5-HT) axon terminals is not understood. Recent studies have implicated MDMA metabolites, but their precise role remains unclear. To further evaluate the relative importance of metabolites versus the parent compound in neurotoxicity, we explored the relationship between pharmacokinetic parameters of MDMA, 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA), and 4-hydroxy-3-methoxymethamphetamine (HMMA) and indexes of serotonergic neurotoxicity in the same animals. We also further evaluated the neurotoxic potential of 5-(N-acetylcystein-S-yl)-HHMA (5-NAC-HHMA), an MDMA metabolite recently implicated in 5-HT neurotoxicity. Lasting serotonergic deficits correlated strongly with pharmacokinetic parameters of MDMA (Cmax and area under the concentration-time curve), more weakly with those of MDA, and not at all with those of HHMA or HMMA (total amounts of the free analytes obtained after conjugate cleavage). HHMA and HMMA could not be detected in the brains of animals with high brain MDMA concentrations and high plasma HHMA and HMMA concentrations, suggesting that HHMA and HMMA do not readily penetrate the blood-brain barrier (either in their free form or as sulfate or glucuronic conjugates) and that little or no MDMA is metabolized to HHMA or HMMA in the brain. Repeated intraparenchymal administration of 5-NAC-HHMA did not produce significant lasting serotonergic deficits in the rat brain. Taken together, these results indicate that MDMA and, possibly, MDA are more important determinants of brain 5-HT neurotoxicity in the rat than HHMA and HMMA and bring into question the role of metabolites (including 5-NAC-HHMA) in MDMA neurotoxicity.

UR - http://www.scopus.com/inward/record.url?scp=70349288389&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349288389&partnerID=8YFLogxK

U2 - 10.1124/dmd.109.028340

DO - 10.1124/dmd.109.028340

M3 - Article

C2 - 19628751

AN - SCOPUS:70349288389

VL - 37

SP - 2079

EP - 2086

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 10

ER -