title: Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells.
abstract: 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differentiated P19 neurons, as measured by intracellular MTT reduction and extracellular LDH activity assays. The P19-derived neurons express both the serotonin reuptake transporter (SERT), that is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A (MAO-A). The involvement of these proteins in the MDMA-induced toxicity was investigated by a pharmacological approach. The MAO inhibitors clorgyline and deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not able to mimic the toxic effects of MDMA in the P19-derived neurons or block the MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced neurotoxicity, but pre-treatment with the antioxidants α-tocopherol or N-acetylcysteine did not reveal any protective effects in the P19 neurons. Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, but MDMA did not alter the mitochondrial membrane potential (ΔΨm) in the P19 neurons. We conclude that MDMA produce a concentration-, time- and temperature-dependent neurotoxicity and our results suggest that the mechanism behind MDMA-induced toxicity in mouse-derived neurons do not involve the serotonergic system, oxidative stress or mitochondrial dysfunction.
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Dina
authors.initials: D
authors.lastname: Popova
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Andréas
authors.initials: A
authors.lastname: Forsblad
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Hashemian
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Stig O P
authors.identifier: http://orcid.org/0000-0001-9740-8499
authors.initials: SO
authors.lastname: Jacobsson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003010:Clorgyline / Q000494:pharmacology; D054278:Embryonal Carcinoma Stem Cells; D005473:Fluoxetine / Q000494:pharmacology; D015870:Gene Expression; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D012642:Selegiline / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; D005473:Fluoxetine; D012642:Selegiline; D008995:Monoamine Oxidase; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D003010:Clorgyline