The neurotoxic effects of methylenedioxymethamphetamine (MDMA) and its metabolites on rat brain spheroids in culture

Rat whole-brain spheroids were used to assess the intrinsic neurotoxicity o f methylenedioxymethamphetamine (MDMA, Ecstasy) and two of its metabolites, dihydroxymethamphetamine (DHMA) and 6-hydroxy-MDMA (6-OH MDMA). Exposure o f brain spheroids to MDMA or the metabolite 6-OH MDMA (up to 500 mu mol/L) for 5 days in culture did not alter intracellular levels of glutathione (GS H), glial fibrillary acidic protein (GFAP) or serotonin (5-HT). In contrast , exposure to the metabolite DHMA, which can deplete intracellular thiols, significantly increased GSH levels (up to 170% of control) following exposu re to 50 and 100 mu mol/L DHMA. There was also a significant reduction in t he levels of glial fibrillary acidic protein (GFAP) and GSH by DHMA at the highest concentration tested (500 mu mol/L) but there was no effect on 5HT. This may constitute a sublethal neurotoxic compensatory response to DHMA i n an attempt to replenish depleted intraneural GSH levels following metabol ite exposure. Rat whole-brain spheroids may thus be a useful in vitro model to delineate mechanisms and effects of this class of neurotoxin.