A study of the mechanisms involved in the neurotoxic action of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine neurones in mouse brain

MDMA (ecstasy) causes long-term damage to dopamine nerve terminals in the mouse striatum, accompanied by acute hyperthermia. Blocking NMDA receptors or using clomethiazole did not protect against this damage. The free radical trap PBN and the nitric oxide synthase inhibitor 7-NI were protective but also lowered body temperature. Two other NOS inhibitors, S-methyl-L-thiocitrulline and AR-R17477AR, provided significant neuroprotection with little effect on hyperthermia. MDMA increased free radical formation in the striatum, which was prevented by AR-R17477AR, which lacks radical-trapping activity. This suggests MDMA neurotoxicity involves radicals from MDMA or dopamine metabolites combining with nitric oxide to form damaging peroxynitrites.

Study at a glance

Abstract

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. British Journal of Pharmacology (2001) 134 , 1711–1723; doi: 10.1038/sj.bjp.0704435