Accumulation of Neurotoxic Thioether Metabolites of 3,4-(±)-Methylenedioxymethamphetamine in Rat Brain

The serotonergic neurotoxicity of 3,4-(±)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N -methyl-α-methyldopamine ( N -Me-α-Me...

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Published in:The Journal of pharmacology and experimental therapeutics 2008-01, Vol.324 (1), p.284-291
Main Authors: Erives, Gladys V, Lau, Serrine S, Monks, Terrence J
Format: Article
Language:English
Subjects:
3,4-Methylenedioxyamphetamine - pharmacokinetics
3,4-Methylenedioxyamphetamine - pharmacology
Animals
Brain - drug effects
Brain - metabolism
Hydroxyindoleacetic Acid - metabolism
Male
Rats
Rats, Sprague-Dawley
Serotonin - metabolism
Serotonin Agents - pharmacokinetics
Serotonin Agents - pharmacology
Sulfides - metabolism
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Summary:The serotonergic neurotoxicity of 3,4-(±)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N -methyl-α-methyldopamine ( N -Me-α-MeDA). Thioether (glutathione and N -acetylcysteine) metabolites of N -Me-α-MeDA are neurotoxic and are present in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, the present study was designed to determine the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA (20 mg/kg s.c.) at 12-h intervals for a total of four injections led to a significant accumulation of the N -Me-α-MeDA thioether metabolites in striatal dialysate. The area under the curve (AUC) 0–300 min for 5-(glutathion- S -yl)- N -Me-α-MeDA increased 33% between the first and fourth injections and essentially doubled for 2,5-bis-(glutathion- S -yl)- N -Me-α-MeDA. Likewise, accumulation of the mercapturic acid metabolites was reflected by increases in the AUC 0–300 min for both 5-( N -acetylcystein- S -yl)- N -Me-α-MeDA (35%) and 2,5-bis-( N -acetylcystein- S -yl)- N -Me-α-MeDA (85%), probably because processes for their elimination become saturated. Indeed, the elimination half-life of 5-( N -acetylcystein- S -yl)- N -Me-α-MeDA and 2,5-bis-( N -acetylcystein- S -yl)- N -Me-α-MeDA increased by 53 and 28%, respectively, between the first and third doses. Finally, although the C max values for the monothioether conjugates were essentially unchanged after each injection, the values increased by 38 and ∼50% for 2,5-bis-(glutathion- S -yl)- N -Me-α-MeDA and 2,5-bis-( N -acetylcystein- S -yl)- N -Me-α-MeDA, respectively, between the first and fourth injections. The data indicate that neurotoxic metabolites of MDMA may accumulate in brain after multiple dosing.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.107.128785