The effects of prior exposure to neurotoxic and non-neurotoxic doses of MDMA on MDMA or cocaine-induced locomotion was examined in three studies performed in Swiss-Webster mice. The researchers first established a neurotoxic regimen by examining the effects of 3 different repeated dose regimens on mortality and brain dopamine and serotonin 5 days after treatment, using twice-daily doses of 40, 30 or 15 mg/kg MDMA given 8 h apart for two days. All three doses produced mortality and reduced brain dopamine, and the highest dose reduced serotonin as well. (HPLC was used to assess dopamine and metabolites in striatum and serotonin and metabolites in frontal cortex, hippocampus and striatum removed 5 days post-drug. Radioligand binding studies assessed dopamine and serotonin transporter levels in the same brain regions collected from the opposite hemisphere). The 15 mg/kg MDMA regimen had the lowest level of mortality (13.5%) and produced approximately 30% reduction in dopamine, dopamine metabolites and dopamine transporter. The second study compared locomotion in response to a second dose of 10 mg/kg MDMA in mice given a single dose of 10 mg/kg MDMA and mice given twice-daily injections of 15 mg/kg MDMA for 2 days, with MDMA given 5, 35, 50 and 80 days after initial MDMA regimen. Both the single and repeated dose regimens produced increased locomotion in response to a subsequent dose of 10 mg/kg MDMA given 5 days post-drug, when compared to saline-treated animals. However, only mice given the 15 mg/kg repeated dose regimen still exhibited greater locomotion than controls after MDMA given 35, 50 and 80 days post-drug. Mice given both single-dose and repeated-dose MDMA regimens showed greater locomotion than controls given 20 mg/kg cocaine 12 days after treatment. Despite making mice more sensitive to subsequent doses of MDMA or cocaine, 10 mg/kg MDMA did not alter striatal dopamine, DA metabolites, or transporter, or frontal and hippocampal serotonin, 5-HT metabolites, or transporter. (Brain monoamines and transporter measured 83 d post-drug, and mice given the repeated-dose regimen still exhibited lower levels of brain dopamine and serotonin). A final experiment examined the effects of a single 20 mg/kg dose of cocaine versus 10 mg/kg given 4 or 5 times on locomotion seen after 10 mg/kg MDMA, with cocaine given 3 days post-drug. Only repeated doses of cocaine produced an increase in locomotion after MDMA. Taken together, it appears that a neurotoxic regimen of MDMA produced long-lasting changes in response to subsequent doses of cocaine or MDMA, with mice exhibiting greater locomotion from 5 to 80 days after initial MDMA treatment. On the other hand, a single dose of 10 mg/kg MDMA produced little to no signs of neurotoxicity and only increased locomotion in response to MDMA 5 days post-drug. However, a single dose of 20 mg/kg cocaine did not produce an equivalent increase in MDMA-induced locomotion 3 d post-drug. Study findings suggest that non-neurotoxic doses of MDMA produce effects on stimulant-induced locomotion similar to those seen after neurotoxic doses, but that these effects have a shorter duration. It is notable that subsequent doses, given 30, 15 and 35 days apart, did not further alter locomotion. Other researchers have also reported behavioral changes after presumably non-neurotoxic doses of MDMA (Taylor and Jensch 2001; Fone et al. 2002). The relevance of these findings to human ecstasy users remains uncertain, particularly since MDMA neurotoxicity in mice is dopamine-related, not serotonin-related. However, it is possible that repeated and high doses of MDMA may either increase the rewarding effects or the stimulant-like effects of MDMA. Study findings also suggest that changes in sensitivity to other drugs seen after MDMA may occur even when the doses are not neurotoxic.