A study of the mechanisms involved in the neurotoxic action of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine neurones in mouse brain
British Journal of Pharmacology – December 01, 2001
Source: OpenAlex
Summary
MDMA administration in mice leads to a staggering 70% loss of striatal dopamine concentration after three doses of 25 mg/kg, highlighting its neurotoxic potential. The study explored various pretreatments for neuroprotection, revealing that nitric oxide synthase inhibitors provided significant protection without exacerbating hyperthermia. Notably, AR-R17477AR (5 mg/kg) effectively prevented free radical formation linked to MDMA's neurotoxicity. This suggests that MDMA-induced damage may stem from radicals interacting with nitric oxide, forming harmful peroxynitrites that contribute to long-term neurodegeneration.
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