A study of the mechanisms involved in the neurotoxic action of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') on dopamine neurones in mouse brain.
1. 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. 2. 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. 3. 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)x3) failed to provide neuroprotection. 4. Pretreatment with clomethiazole (50 mg kg(-1)x3) was similarly ineffective in protecting against MDMA-induced dopamine loss. 5. The free radical trapping compound PBN (150 mg kg(-1)x3) was neuroprotective, but it proved impossible to separate neuroprotection from a hypothermic effect on body temperature. 6. Pretreatment with the nitric oxide synthase (NOS) inhibitor 7-NI (50 mg kg(-1)x3) produced neuroprotection, but also significant hypothermia. Two other NOS inhibitors, S-methyl-L-thiocitrulline (10 mg kg(-1)x3) and AR-R17477AR (5 mg kg(-1)x3), provided significant neuroprotection and had little effect on MDMA-induced hyperthermia. 7. 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.
Colado
M I
MI
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain.
Camarero
J
J
Mechan
A O
AO
Sanchez
V
V
Esteban
B
B
Elliott
J M
JM
Green
A R
AR
D000818:Animals; D002719:Chlormethiazole / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003497:Cyclic N-Oxides; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced; D005609:Free Radicals; D062385:Hydroxybenzoates / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D017551:Microdialysis; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009589:Nitrogen Oxides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020156:Salicylic Acid / Q000378:metabolism
D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D005609:Free Radicals; D062385:Hydroxybenzoates; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D011725:Pyridines; C096406:alpha-phenyl-2-pyridineethanamine dihydrochloride; D002719:Chlormethiazole; C029217:phenyl-N-tert-butylnitrone; D016291:Dizocilpine Maleate; C009135:2,3-dihydroxybenzoic acid; D019001:Nitric Oxide Synthase; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D020156:Salicylic Acid; D004298:Dopamine