Glial cell response to 3,4-(±)-methylenedioxymethamphetamine and its metabolites

Joseph M. Herndon, Aram B. Cholanians, Serrine Lau, Terrence Monks

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

3,4-(±)-Methylenedioxymethamphetamine (MDMA) and 3,4-(±)-methylenedioxyamphetamine (MDA), a primary metabolite of MDMA, are phenylethylamine derivatives that cause serotonergic neurotoxicity. Although several phenylethylamine derivatives activate microglia, little is known about the effects of MDMA on glial cells, and evidence of MDMA-induced microglial activation remains ambiguous. We initially determined microglial occupancy status of the parietal cortex in rats at various time points following a single neurotoxic dose of MDMA (20 mg/ kg, SC). A biphasic microglial response to MDMA was observed, with peak microglial occupancy occurring 12- and 72-h post-MDMA administration. Because direct injection of MDMA into the brain does not produce neurotoxicity, the glial response to MDMA metabolites was subsequently examined in vivo and in vitro. Rats were treated with MDA (20 mg/kg, SC) followed by ex vivo biopsy culture to determine the activation of quiescent microglia. A reactive microglial response was observed 72 h after MDA administration that subsided by 7 days. In contrast, intracerebroventricular (ICV) administration of MDA failed to produce a microglial response. However, thioether metabolites of MDA derived from α-methyldopamine (α-MeDA) elicited a robust microglial response following icv injection. We subsequently determined the direct effects of various MDMA metabolites on primary cultures of E18 hippocampal mixed glial and neuronal cells. 5-(Glutathion-S-yl)-α-MeDA, 2,5-bis-(glutathion-S-yl)-α-MeDA, and 5-(N-acetylcystein-S-yl)-α-MeDA all stimulated the proliferation of glial fibrillary acidic protein-positive astrocytes at a dose of 10μM. The findings indicate that glial cells are activated in response to MDMA/MDA and support a role for thioether metabolites of α-MeDA in the neurotoxicity.

Original languageEnglish (US)
Article numberkft275
Pages (from-to)130-138
Number of pages9
JournalToxicological Sciences
Volume138
Issue number1
DOIs
StatePublished - Mar 2014

Fingerprint

N-Methyl-3,4-methylenedioxyamphetamine
Metabolites
Neuroglia
3,4-Methylenedioxyamphetamine
Phenethylamines
Microglia
Sulfides
Glutathione
Rats
Deoxyepinephrine
Chemical activation
Derivatives
Parietal Lobe
Injections
Biopsy
Glial Fibrillary Acidic Protein
Direct injection
Astrocytes
Brain

Keywords

  • 3,4-(±)-methylenedioxymethamphetamine
  • metabolites
  • Microglial activation

ASJC Scopus subject areas

  • Toxicology

Cite this

Glial cell response to 3,4-(±)-methylenedioxymethamphetamine and its metabolites. / Herndon, Joseph M.; Cholanians, Aram B.; Lau, Serrine; Monks, Terrence.

In: Toxicological Sciences, Vol. 138, No. 1, kft275, 03.2014, p. 130-138.

Research output: Contribution to journalArticle

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