A study of the mechanisms involved in the neurotoxic action of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine neurones in mouse brain
María Isabel Colado, Jorge Camarero, Annis O. Mechan, Verónica Sánchez, B. Moreno Esteban, J.m. Elliott, Alfred Richard Green
British Journal of Pharmacology December 1, 2001 DOI: 10.1038/sj.bjp.0704435 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | MDMA clomethiazole PBN |
| Dose | MDMA 25 mg/kg ×3, AR-R15896AR 20/5/5 mg/kg, MK-801 0.5 mg/kg ×3, clomethiazole 50 mg/kg ×3, PBN 150 mg/kg ×3, 7-NI 50 mg/kg ×3, S-methyl-L-thiocitrulline 10 mg/kg ×3, AR-R17477AR 5 mg/kg ×3 |
| Duration | 7 days after MDMA administration |
| Topics | MDMA |
| Keywords | Neuroprotection Dopamine Pharmacology Microdialysis Neurotoxicity Methamphetamine Hyperthermia Striatum Anesthesia |
| Citations | 122 |
| Key findings | MDMA-induced striatal dopamine neurotoxicity in mice is mediated by free radicals combining with nitric oxide to form peroxynitrites, and can be prevented by nitric oxide synthase inhibitors without affecting hyperthermia. |
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