A study of the mechanisms involved in the neurotoxic action of 34-methylenedioxymethamphetamine (MDMA ‘ecstasy) on dopamine neurones in mouse brain

摘要

class="enumerated" style="list-style-type:decimal">Administration of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy') to mice produces acute hyperthermia and long-term degeneration of striatal dopamine nerve terminals. Attenuation of the hyperthermia decreases the neurodegeneration. We have investigated the mechanisms involved in producing the neurotoxic loss of striatal dopamine.MDMA produced a dose-dependent loss in striatal dopamine concentration 7 days later with 3 doses of 25 mg kg⁻¹ (3 h apart) producing a 70% loss.Pretreatment 30 min before each MDMA dose with either of the N-methyl-D-aspartate antagonists AR-R15896AR (20, 5, 5 mg kg⁻¹) or MK-801 (0.5 mg kg⁻¹×3) failed to provide neuroprotection.Pretreatment with clomethiazole (50 mg kg⁻¹×3) was similarly ineffective in protecting against MDMA-induced dopamine loss.The free radical trapping compound PBN (150 mg kg⁻¹×3) was neuroprotective, but it proved impossible to separate neuroprotection from a hypothermic effect on body temperature.Pretreatment with the nitric oxide synthase (NOS) inhibitor 7-NI (50 mg kg⁻¹×3) produced neuroprotection, but also significant hypothermia. Two other NOS inhibitors, S-methyl-L-thiocitrulline (10 mg kg⁻¹×3) and AR-R17477AR (5 mg kg⁻¹×3), provided significant neuroprotection and had little effect on MDMA-induced hyperthermia.MDMA (20 mg kg⁻¹) increased 2,3-dihydroxybenzoic acid formation from salicylic acid perfused through a microdialysis tube implanted in the striatum, indicating increased free radical formation. This increase was prevented by AR-R17477AR administration. Since AR-R17477AR was also found to have no radical trapping activity this result suggests that MDMA-induced neurotoxicity results from MDMA or dopamine metabolites producing radicals that combine with NO to form tissue-damaging peroxynitrites.