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BACKGROUND: 3, 4-methylenedioxymethamphetamine (MDMA, also known as ecstasy) has been shown to exhibit neurotoxic effects on the hippocampus. However, exposure to sub-lethal insults of MDMA has been reported to result in neuroprotection.OBJECTIVE: To investigate the effects of MDMA on hippocampal neuronal viability, caspase-3 activity, and mRNA expression of the N-methyI-D-aspartate (NMDA) receptor 2B (NR2B) subunit.DESIGN, TIME AND SETTING: A cytological, in vitro experiment was performed at the Department of Anatomy, School of Medicine, and Department of Toxicology-Pharmacology, Faculty of Pharmacy,Tehran University of Medical Sciences in 2008.MATERIALS: MDMA was extracted from ecstasy tablets, which were kindly supplied by the Pharmacology-Toxicology Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Iran.METHODS: Hippocampal neurons were isolated from Wistar rats at gestational day 18. Following primary culture, hippocampal neuronal viability was detected by MTT assay. Varying concentrations of MDMA (100-5 000 μmol/L) were used to determine lethal concentration 50 (LC_(50)), which was around 1 500 μmol/L. Five concentrations of MDMA below 1 500 μmol/L (100, 200, 400, 800, and 1 050 μmol/L) were used for the remaining experiments. After 24 hours of MDMA treatment,NR2B mRNA expression was detected by RT-PCR, and caspase-3 relative activity was determined by colorimetric assay.MAIN OUTCOME MEASURES: Hippocampal neuronal viability, caspase-3 activity, and NR2B mRNA expression.RESULTS: MDMA-induced neurotoxicity in hippocampal neuronal cultures was dose-dependent. In high concentrations (1 000-5 000 μmol/L) of MDMA, neuronal viability was decreased. However,with a 500 μmol/L dose of MDMA, neuronal viability was significantly increased (P < 0.01). Low concentrations of MDMA (200 and 400 μmol/L) significantly decreased caspase-3 activity (P < 0.01),whereas high concentrations of MDMA significantly increased caspase-3 activity (P < 0.01). NR2B subunit mRNA expression was not significantly altered after 100-1 050 μmol/L MDMA exposure.CONCLUSION: MDMA exhibits dual effects on hippocampal neuronal viability and caspase-3 activity. These effects are independent from NR2B subunit expression levels.