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Superoxide radicals mediate the biochemical effects of methylenedioxymethamphetamine (MDMA): evidence from using
J L Cadet1, B Ladenheim, H Hirata
1Molecular Neuropsychiatry Section, NIH/NIDA, Baltimore, Maryland 21224, USA.
Abstract:
The subacute and long-term biochemical effects of methylenedioxymethamphetamine (MDMA) were assessed in homozygous and heterozygous transgenic (Tg) mice that carry the complete sequence of the human copper-zinc (CuZn) superoxide dismutase (SOD) gene. Non-transgenic (Non-Tg) mice showed significant decreased in striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels both at 24 h and at 2 weeks after a single injection of MDMA (50 mg/kg). Heterozygous SOD-Tg mice showed DA depletion only at the 24 h time point. In contrast, homozygous SOD-Tg mice show no DA or DOPAC depletion at either the 24 h or at the 2 week time points. Moreover, three injections of MDMA (50 mg/kg) given 24 h apart also caused marked reduction of striatal DA and DOPAC in Non-Tg mice when these substances were measured 2 weeks after the last MDMA injection. That injection schedule also caused small decreases in DA levels in the heterozygous animals but no changes in the homozygous mice; DOPAC levels were not affected in the heterozygous nor in the homozygous SOD-Tg mice. Furthermore, the multiple injection schedule caused significant decreases in DA and DOPAC in female Non-Tg mice but not in the two strains of transgenic mice. Neither the single dose nor the multiple dose schedule of MDMA injections affected striatal serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels in any of the three strains of mice. These results support previous observations that MDMA-induced biochemical effects are observed in the DA systems of mice, whereas these effects are seen in the 5-HT systems of rats. The present observations also document for the first time a role for the production of superoxide radicals in these effects of MDMA. These mice are an important tool for dissecting pathways involved in drug-induced neurotoxicity.
Insights
Methylenedioxymethamphetamine (MDMA) neurotoxicity in mice is linked to superoxide radicals. Transgenic mice with human copper-zinc superoxide dismutase (SOD) genes show reduced MDMA-induced dopamine depletion, suggesting a protective role for SOD.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Methylenedioxymethamphetamine (MDMA) is known to cause neurotoxic effects.
- The role of oxidative stress in MDMA neurotoxicity is an area of ongoing research.
- Copper-zinc superoxide dismutase (CuZnSOD) is a key antioxidant enzyme.
Purpose of the Study:
- To investigate the subacute and long-term biochemical effects of MDMA.
- To assess the impact of human copper-zinc superoxide dismutase (CuZnSOD) gene expression on MDMA neurotoxicity.
- To explore the role of superoxide radicals in MDMA-induced neurochemical changes.
Main Methods:
- Utilized homozygous and heterozygous transgenic (Tg) mice expressing the human CuZnSOD gene.
- Administered single and multiple doses of MDMA (50 mg/kg) to Tg and non-transgenic (Non-Tg) mice.
- Measured striatal dopamine (DA), dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) levels at different time points.
Main Results:
- Non-Tg mice showed significant DA and DOPAC depletion after MDMA exposure.
- Heterozygous Tg mice exhibited transient DA depletion, while homozygous Tg mice showed no significant depletion.
- MDMA did not affect striatal 5-HT or 5-HIAA levels in any mouse group.
- Multiple MDMA doses exacerbated DA and DOPAC depletion in female Non-Tg mice.
Conclusions:
- Homozygous transgenic mice overexpressing human CuZnSOD are protected against MDMA-induced dopamine depletion.
- These findings highlight the critical role of superoxide radical production in MDMA neurotoxicity.
- Transgenic mouse models expressing human CuZnSOD are valuable tools for studying drug-induced neurotoxicity pathways.