title: Ecstasy induces apoptosis via 5-HT(2A)-receptor stimulation in cortical neurons.
abstract: 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a psychoactive and hallucinogenic drug of abuse. MDMA has been shown to produce neurotoxicity both in animals and humans. MDMA and other amphetamines induce serotonergic and dopaminergic terminal neurotoxicity and also neurodegeneration in areas including the cortex, hippocampus, striatum and thalamus. Herein, we investigated the mechanisms involved in MDMA-induced neurotoxicity to neuronal serum free cultures from rat cortex. The hyperthermic effect produced by MDMA has been shown to be a clinically relevant aspect for the neurotoxic events. Thus, MDMA-induced toxicity to cortical neurons was evaluated both under normothermic (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Our findings showed that MDMA produced neuronal apoptosis, accompanied by activation of caspase 3, in a concentration dependent manner. MDMA neurotoxicity was completely prevented by pre-treatment with a 5-HT(2A)-receptor antibody, which acted as an "irreversible non-competitive antagonist" of this receptor. Furthermore, MDMA depleted intracellular glutathione (GSH) levels in a concentration dependent manner, an effect that was attenuated by Ketanserin, a competitive 5-HT(2A)-receptor antagonist. Accordingly, N-acetylcysteine, an antioxidant and GSH precursor, also reduced MDMA-induced toxicity. Specific inhibitors of the inducible and neuronal nitric oxide synthase (NOS) partially prevented MDMA neurotoxicity, ascertaining the involvement of reactive nitrogen species, in the toxic effect. In conclusion, direct MDMA 5-HT(2A)-receptor stimulation produces intracellular oxidative stress that leads to neuronal apoptosis accompanied by caspase 3 activation.
authors.affiliation: REQUIMTE, Toxicology Department, Faculty of Pharmacy, University of Porto, Rua Aníbal Cunha 164, 4099/030 Porto, Portugal. joaocapela@ff.up.pt
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Capela
authors.forename: Eduarda
authors.initials: E
authors.lastname: Fernandes
authors.forename: Fernando
authors.initials: F
authors.lastname: Remião
authors.forename: Maria Lourdes
authors.initials: ML
authors.lastname: Bastos
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000276:immunology / Q000502:physiology*; D018490:Serotonin Agents / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D004791:Enzyme Inhibitors; D044402:Receptor, Serotonin, 5-HT2A; D018490:Serotonin Agents; D053148:Caspase 3; D018817:N-Methyl-3,4-methylenedioxyamphetamine