BRAIN * RESEARCH ELSEVIER Brain Research 655 (1994) 259-262 :. Short communication -_ CuZn-superoxide dismutase (CuZnSOD) transgenic mice show resistance to the lethal effects of methylenedioxyamphetamine (MDA) and ofmethylenedioxymethamphetamine(MDMA) . Jean Lud Cadet a,., Bruce Ladenheim a, Ira Baum a, Elaine Carlson b, Charles Epstein b a Molecular NeuropsychiatrySection, NIH /NIDA, Addiction Research Center,Baltimore, MD 21224, USA b Departmentof Pediatrics, Unicersity of California, San Francisco, CA 94143,USA c Accepted 14 June 1994 Abstract __, We have used female and male transgenic (Tg) mice that carry the complete sequence of the human copper-zinc (CuZn) , superoxide dismutase (SOD) gene in order to assess the lethal effects of methylenedioxyamphetamine (MDA) and methylene- ,_ im dioxymethamphetamine (MDMA). In contrast to non-Tg mice, both heterozygous and homozygous SOD-Tg mice showed resistance to the lethal effects of both drugs. Females of both SOD-Tg and non-Tg strains were somewhat more resistant to the _? ;._ effects of these drugs in comparison to males. In general, homozygous animals show greater resistance to the effects of the two ,, drugs. These results suggest that the acute lethal effects of amphetamine-substituted analogs might involve the intracellular '.i overproduction of the superoxide radicals secondary to hypoxic injury. The gender differences suggest that there might be _' - 4 hormonal-free radical scavenger interactions that offer better protection to female mice. This might be related both to the _l _ lifespan of and to the lower prevalence of Parkinson's disease in women. Future studies will need to address these issues further. 3 Key words: Transgenic mouse; Superoxide dismutase; Methylenedioxyamphetamine; Methylenedioxymethamphetamine; Lethal- iD ! ity;Freeradical _ _'' · Oxidative stress and oxygen free radicals are thought the toxic manifestations of methamphetamine [3] and to play an important role in both the acute and chronic MPTP [20] and have shown that the toxic effects of effects of a number of neurotoxic processes. These these drugs are attenuated in these animals. ::.. include administration of some drugs, radiation-in- Methylenedioxyamphetamine (MDA) and meth- duced injury, as well as oxygen-induced injury to the ylenedioxymethamphetamine (MDMA) are drugs of central nervous system [1,3] (see refs. for a comprehen- abuse that affect the monoaminergic systems of ro- sive review). Despite the belief that oxygen free radi- dents [8,15,22] and of non-human primates [21]. In >_,, cals are of importance in a variety of pathological addition to their neurotoxic effects in the brain, these processes affecting the nervous system, it has not al- drugs cause acute lethality at high doses [12]. The ways been possible to examine their roles directly, mechanisms for this acute toxicity are not understood However, transgenic animal technology has made it but might involve deleterious effects on the cardiovas- possible to constitutively increase the level of cytosolic cular or central nervous system [17]. In the central CuZnSOD [9], an enzyme which is in the first line of nervous system, these could include seizures with sec- 1 defense against oxygen-based radicals such as the su- ondary anoxic events. These occurrences might be ac- 2.: peroxide anion (02) [10]. We have used these mice in companied by the intracellular generation of high lev- order to evaluate the role of oxygen-based radicals in els of superoxide radicals, hydrogen peroxide, or hy- _ droxyl radicals [7]. As a first step towards assessing the role of free radicals in the neurotoxic events associated with the use of MDA and MDMA, we have used * Corresponding author. Molecular Neuropsychiatry Section, .. _-, NIH/NIDA, Addiction Research Center, P.O. Box 5180, Baltimore, CuZnSOD-Tg mice in order to investigate acute reac- .. MD 21224, USA. Fax: (1) (410) 550-2745. tions to various doses of MDA and MDMA. We also 0006-8993/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0006-8993(94)00707-J //1 I_ ....,m