Serotonin transporter expression is not sufficient to confer cytotoxicity to 3,4-methylenedioxymethamphetamine (MDMA) in vitro

Abstract

There is much evidence from animal studies that the recreational drug MDMA is a selective toxin which damages serotonin nerve terminals and axons. These in vivostudies show that an interaction between MDMA and the serotonin transporter protein (SERT) is the .rst step in toxicity. To further our understanding of the biochemical processes of MDMA toxicity we wished to use an in vitromodel for toxicity. We produced two COS-7 cell lines with different levels of expression of recombinant rat SERT, as determined by 5-HT uptake assays, and compared them to human SERTexpressing JAR cells and to untransfected COS-7 cells which do not express SERT. Cultured cells were exposed to MDMA (0.1 µ Mñ1mM) for 24 or 48 h at 37 °C before assessing cytotoxicity by LDH release and MTT turnover. Only at the highest concentration used, 1mM, was MDMA cytotoxic, and this toxicity was found in all cell lines. Cytotoxicity caused by 48 h exposure to 1mM MDMA at 37 °C was not related to the level of SERT expression, not blocked by the SERT-blocking drugs paroxetine or .uoxetine and not enhanced, in JAR cells, by forskolin preincubation that increased 5-HT uptake capacity by 50%. We conclude that SERT expression is not suf.cient to confer MDMA toxicity to cell lines. Therefore SERT-expressing cell lines do not offer a simple model system to elucidate the mechanisms underlying MDMA toxicity.