Superoxide radicals mediate the biochemical effects of methylenedioxymethamphetamine (MDMA): Evidence from using CuZn‐superoxide dismutase transgenic mice
Jean Lud Cadet, Bruce Ladenheim, Hiroshi Hirata, Richard B Rothman, Syed F. Ali, Elaine Carlson, Charles B. Epstein, Timothy H. Moran
Synapse October 1, 1995 DOI: 10.1002/syn.890210210 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled experiment using genetically modified mice Peer reviewed |
|---|---|
| Population | Homozygous and heterozygous transgenic mice carrying the human copper-zinc superoxide dismutase gene, and non-transgenic mice |
| Intervention | MDMA |
| Dose | 50 mg/kg |
| Duration | 24 hours and 2 weeks after single injection; 2 weeks after last of three injections given 24 hours apart |
| Topics | MDMA |
| Keywords | Superoxide dismutase Radical Pharmacology Genetically modified mouse Transgene Biochemistry |
| Citations | 81 |
| Key findings | Overexpression of human copper-zinc superoxide dismutase protects against MDMA-induced dopamine depletion in mouse striatum, implicating superoxide radicals in the neurotoxic mechanism. |
Abstract
Abstract The subacute and long‐term biochemical effects of methylenedioxymeth‐amphetamine (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‐HIM)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. © 1995 Wiley‐Liss, Inc. 1 This article is a US Government work and, as such, is in the public domain in the United States of America.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 22
- Persistent MDMA‐induced dopaminergic neurotoxicity in the striatum and substantia nigra of mice Journal of Neurochemistry September 24, 2008
- Glutathione and N-Acetylcysteine Conjugates of α-Methyldopamine Produce Serotonergic Neurotoxicity: Possible Role in Methylenedioxyamphetamine-Mediated Neurotoxicity Chemical Research in Toxicology November 19, 1999
- The mechanisms involved in the long‐lasting neuroprotective effect of fluoxetine against MDMA (‘ecstasy’)‐induced degeneration of 5‐HT nerve endings in rat brain British Journal of Pharmacology September 1, 2001
- Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT Synapse 2001
- Pro‐oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes British Journal of Pharmacology April 21, 2011
and 17 more in the library
Cites 11
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- Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Journal of Pharmacology and Experimental Therapeutics 1987
- 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Journal of Pharmacology and Experimental Therapeutics September 1, 1987
- CuZn-superoxide dismutase (CuZnSOD) transgenic mice show resistance to the lethal effects of methylenedioxyamphetamine (MDA) and of methylenedioxymethamphetamine (MDMA). Brain Research August 1, 1994
- Effect of acute monoamine depletion on 3,4-methylenedioxymethamphetamine-induced neurotoxicity. Pharmacology, Biochemistry, and Behavior July 1, 1993
and 6 more in the library