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

Abstract

The serotonergic neurotoxicity of 3,4-(Ϯ)-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-␣-methyldopamine (N-Me-␣-MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-␣-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. The serotonergic neurotoxicity 3,4-(Ϯ)-methylenedioxymethamphetamine (MDMA, Ecstasy) and 3,4-(Ϯ)-methylenedioxyamphetamine (MDA) is dependent on the route of administration (O'Shea et al., 1998). Direct injection of MDMA and MDA into the brain fails to reproduce the acute or long-term neurotoxic effects evident following peripheral administration of these drugs (Schmidt et al., 1987;Paris and Cunningham, 1992), suggesting that systemic (liver) metabolism contributes to the neurotoxicity of MDMA and MDA. Indeed, although MDMA targets the serotonergic system in humans, nonhuman primates, and rats, the finding that MDMA does not affect the serotonergic system in mice but rather targets the dopaminergic system has been attributed to metabolic differences between species (Logan et al., 1988;Escobedo et al., 2005). Perhaps the most convincing evidence that peripheral metabolism of MDMA is required for neurotoxicity was provided by the work of Esteban et al. (2001). In this study, MDMA was perfused into the hippocampus in amounts sufficient to give rise to the range of concentrations observed following peripheral administration of neurotoxic doses of MDMA. After perfusion, acute monoamine release was observed in the absence of long term depletions in 5-HT levels. These data are consistent with the hypothesis that peripheral generation of neurotoxic metabolites contributes to MDMA-induced serotonergic neurotoxicity.MDMA is N-demethylated to MDA and O-demethylenated to N-methyl-␣-methyldopamine (N-Me-␣-MeDA) (Fig. 1) (Lin et al., 1992). N-Demethylation in humans is a minor metabolic pathway (ϳ10%), but ␣-MeDA is a metabolite of both MDMA and MDA. Isoenzymes belonging to the CYP2D subfamily, and the CYP2B or CYP3A1 isoforms, catalyze the low-and high-K m O-demethylenation reactions, respectively (de la Torre et al., 2004). The catecholamine metabolites are very unstable and are either conjugated with sulfate/glucArticle, publication date, and citation information can be found at

Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity

“…The thioether metabolite of HHMA, 5-NAC-HHMA, has been directly implicated in MDMA neurotoxicity (Jones et al, 2005;Erives et al, 2008). In the present study, 5-NAC-HHMA, when administered repeatedly and in large doses into the striatum did not lead to statistically significant 5-HT depletions.…”

“…Because previous research has implicated the catechol thioether metabolite of MDMA, 5-NAC-HHMA, in MDMA neurotoxicity (Jones et al, 2005;Erives et al, 2008), we also performed studies to further assess the 5-HT neurotoxic potential of 5-NAC-HHMA and its selectivity. In these studies, we administered 5-NAC-HHMA directly into the striatum, at two different doses (21 and 42 nmol).…”

“…More recently, other glutathione and N-acetylcysteine conjugates of catechol metabolites of MDMA and MDA have been identified and implicated in MDMA neurotoxicity (Miller et al, 1997;Bai et al, 1999;Jones et al, 2005;Capela et al, 2007;Pizarro et al, 2008). Of these, 5-(N-acetylcystein-S-yl)-N-methyl-␣-methyldopamine [here designated as 5-(N-acetylcystein-S-yl)-HHMA (5-NAC-HHMA)] has been the metabolite most strongly implicated (Jones et al, 2005;Erives et al, 2008).…”

Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) and Its Major Metabolites in Squirrel Monkeys at Plasma Concentrations of MDMA That Develop After Typical Psychoactive Doses

“…With specific reference to brain serotonin neurotoxicity, it remains to be determined whether MDMA or one of its metabolites is primarily responsible. Some findings point to (but do not establish) the importance of the parent compound (dose dependence, high correlation between MDMA levels, and subsequent serotonin neurotoxicity) (see Mechan et al, 2006), whereas others suggest a possible role for metabolites (Monks et al, 2004;Erives et al, 2008). By exploring the relationship among MDMA, its metabolites, and serotonin neurotoxicity in the same animal in the context of nonlinear MDMA accumulation, it should be possible to begin discerning the relative importance of MDMA versus metabolites in the neurotoxic process.…”

Pharmacodynamic interactions between MDMA and concomitants in MDMA tablets on extracellular dopamine and serotonin in the rat brain

“…Increases in MDMA-induced dopamine and 5-HT release, and the neurotoxicity of 5-HT by MDMA, suggest the involvement of MDMA metabolites (Escobedo et al, 2005;Erives et al, 2008;Colad et al, 2004) and the formation of reactive oxygen species (Erives et al, 2008;Gudelsky and Yamamoto, 2008;Quinton and Yamamoto, 2006). Clarification of the mechanism of drug interactions with MDMA, especially with respect to metabolism and the formation of reactive oxygen species, will require further study.…”