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Inhibition of 3,4‐methylenedioxymethamphetamine metabolism leads to marked decrease in 3,4‐dihydroxymethamphetamine formation but no change in serotonin neurotoxicity: Implications for mechanisms of neurotoxicity
Author(s) -
Mueller Melanie,
Yuan Jie,
Maldonado Adrian Concepcion,
Mccann Una D.,
Ricaurte George A.
Publication year - 2011
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20925
Subject(s) - mdma , neurotoxicity , chemistry , ecstasy , pharmacology , serotonin , metabolite , dextromethorphan , saline , p chloroamphetamine , toxicity , biochemistry , endocrinology , serotonergic , psychology , medicine , receptor , organic chemistry , psychiatry
3,4‐Methylenedioxymethamphetamine (MDMA)'s O ‐demethylenated metabolite, 3,4‐dihydroxymethamphetamine (HHMA), has been hypothesized to serve as a precursor for the formation of toxic catechol‐thioether metabolites (e.g., 5‐ N ‐acetylcystein‐ S ‐yl‐HHMA) that mediate MDMA neurotoxicity. To further test this hypothesis, HHMA formation was blocked with dextromethorphan (DXM), which competitively inhibits cytochrome P450 enzyme‐mediated O ‐demethylenation of MDMA to HHMA. In particular, rats were randomly assigned to one of four treatment groups ( n = 9–12 per group): (1) Saline/MDMA; (2) DXM/MDMA; (3) DXM/Saline; (4) Saline/Saline. During drug exposure, time‐concentration profiles of MDMA and its metabolites were determined, along with body temperature. One week later, brain serotonin (5‐HT) neuronal markers were measured in the same animals. DXM did not significantly alter core temperature in MDMA‐treated animals. A large (greater than 70%) decrease in HHMA formation had no effect on the magnitude of MDMA neurotoxicity. These results cast doubt on the role of HHMA‐derived catechol‐thioether metabolites in the mechanism of MDMA neurotoxicity. Synapse, 2011. © 2011 Wiley‐Liss, Inc.