Further Studies on the Role of Metabolites in (±)-3,4-Methylenedioxymethamphetamine-Induced Serotonergic Neurotoxicity
| Autor: | George A. Ricaurte, Martine Largeron, Una D. McCann, Frank T. Peters, Jie Yuan, Hans H. Maurer, Anne Felim, Melanie Mueller, Anne Neudorffer |
|---|---|
| Přispěvatelé: | Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5) |
| Rok vydání: | 2009 |
| Předmět: |
Male
Serotonin Neurotoxicity Syndrome [SDV]Life Sciences [q-bio] N-Methyl-3 4-methylenedioxyamphetamine Metabolite Pharmaceutical Science Pharmacology Serotonergic 030226 pharmacology & pharmacy Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Dopamine mental disorders medicine Animals ComputingMilieux_MISCELLANEOUS 3 4-Methylenedioxyamphetamine Chemistry Neurotoxicity MDMA Articles medicine.disease Rats 3. Good health Deoxyepinephrine Disease Models Animal [SDV.TOX]Life Sciences [q-bio]/Toxicology [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Neurotoxicity Syndromes psychological phenomena and processes 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Drug Metabolism and Disposition Drug Metabolism and Disposition, American Society for Pharmacology and Experimental Therapeutics (ASPET), 2009, 37 (10), pp.2079-2086. ⟨10.1124/dmd.109.028340⟩ |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.109.028340 |
| Popis: | 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 (C(max) 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|