Short- and long-term effects of MDMA ("ecstasy") on synaptosomal and vesicular uptake of neurotransmitters in vitro and ex vivo
by
Bogen IL, Haug KH, Myhre O, Fonnum F.
Division for Protection and Material,
Norwegian Defence Research Establishment,
P.O. Box 25, N-2027, Kjeller, Norway
Neurochem Int 2003 Oct;43(4-5):393-400
ABSTRACT3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a commonly abused drug which has been shown to be neurotoxic to serotonergic neurons in many species. The exact mechanism responsible for the neurotoxicity of MDMA is, however, poorly understood. In this study, the effects of MDMA on the synaptosomal and vesicular uptake of neurotransmitters were investigated. Our results show that MDMA (0.5-20&mgr;M) reduces both synaptosomal and vesicular uptake of serotonin and dopamine in a dose dependent manner in vitro, while the uptake of glutamate and gamma-aminobutyric acid (GABA) remains unaffected. Ex vivo experiments support the importance of the monoamines, with predominant dopaminergic inhibition at short-term exposure (3 x 15mg/kg; 2-h intervals), and exclusively serotonergic inhibition at long-term exposure (2 x 10mg/kg per day; 4 days). This study also compares MDMA and the structurally related antidepressant paroxetine, in an attempt to reveal possible cellular mechanisms for the serotonergic toxicity of MDMA. One important difference between paroxetine and MDMA is that only MDMA has the capability of inhibiting vesicular uptake of monoamines at doses used. We suggest that inhibition of the vesicular monoamine transporter-2, and a following increase in cytoplasmatic monoamine concentrations, might be crucial for the neurotoxic effect of MDMA.Oxidative stress
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