Superoxide radicals mediate the biochemical effects of methylenedioxymethamphetamine (MDMA): evidence from using CuZn-superoxide dismutase transgenic mice.
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.
Cadet
J L
JL
Molecular Neuropsychiatry Section, NIH/NIDA, Baltimore, Maryland 21224, USA.
Ladenheim
B
B
Hirata
H
H
Rothman
R B
RB
Ali
S
S
Carlson
E
E
Epstein
C
C
Moran
T H
TH
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D011954:Receptors, Dopamine / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D013481:Superoxides / Q000378:metabolism*; D014018:Tissue Distribution
D011954:Receptors, Dopamine; D015102:3,4-Dihydroxyphenylacetic Acid; D013481:Superoxides; C079213:RTI 121; D013482:Superoxide Dismutase; D003042:Cocaine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine