Ecstasy induces apoptosis via 5-HT(2A)-receptor stimulation in cortical neurons.
João Paulo Capela, Eduarda Fernandes, Fernando Remião, Maria Lourdes Bastos, Andreas Meisel, Félix Carvalho
Neurotoxicology July 2007 DOI: 10.1016/j.neuro.2007.04.005 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Laboratory study Peer reviewed |
|---|---|
| Population | Rat cortical neurons in serum-free culture |
| Interventions | MDMA 5-HT(2A)-receptor antibody Ketanserin N-acetylcysteine |
| Topics | MDMA |
| Key points | MDMA induces concentration-dependent apoptosis in rat cortical neurons via 5-HT(2A) receptor stimulation, leading to glutathione depletion and oxidative stress; this is prevented by a 5-HT(2A) antibody and attenuated by ketanserin and N-acetylcysteine. |
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.