Amiloride, a drug that blocks sodium/calcium and sodium/hydrogen exchange, worsens long-term serotonin loss caused by MDMA in rats. Unlike with methamphetamine, amiloride also increases MDMA-induced hyperthermia. The antidepressant fluoxetine fully protects against serotonin depletion without affecting hyperthermia, while calcium channel blockers do not. The effect appears mediated by sodium/hydrogen exchange blockade, as dimethylamiloride produces similar results. When rats are kept at 15°C, hyperthermia does not develop and serotonin levels remain normal after seven days. These findings suggest that amiloride's enhancement of serotonin loss depends on its ability to amplify MDMA-induced hyperthermia, and that blocking sodium/hydrogen exchange may combine with hyperthermia to make serotonin nerve endings more vulnerable.
MDMA (ecstasy) causes long-lasting reductions in markers of serotonin neurons in animal brains, including decreased tryptophan hydroxylase activity, lower serotonin and its metabolite 5-HIAA, and reduced binding to serotonin transporters. Similar reductions in 5-HIAA and serotonin transporter density have been observed in human ecstasy users, suggesting loss of serotonergic fibers. However, some recent studies failed to show loss of the serotonin transporter protein or reactive astrogliosis after MDMA exposure, and MDMA also down-regulates serotonin transporter gene expression. These findings have led to debate: decreased protein levels do not necessarily indicate neurodegeneration, but neuromodulatory mechanisms do not rule out serotonin terminal degeneration.