Ecstasy induces apoptosis via 5-HT2A-receptor stimulation in cortical neurons

• Type: Article in International Scientific Journal
• Date: 2007

Authors

Joao Paulo Capela (Author) Other; Eduarda Fernandes (Author) FFUP; Fernando Remiao (Author) FFUP; Maria Lourdes Bastos (Author) FFUP; Andreas Meisel (Author) Other; Felix Carvalho (Author) FFUP

Journal

Title: NeuroToxicology

Vol. 28 No. 4

Pages: 868-875

ISSN: 0161-813X

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 62 Citations

Scopus - 65 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-004-96R

DOI: 10.1016/j.neuro.2007.04.005

Abstract (EN): 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-HT2A-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-HT2A-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-HT2A-receptor stimulation produces intracellular oxidative stress that leads to neuronal apoptosis accompanied by caspase 3 activation.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8