Differential role of dose and environment in initiating and intensifying neurotoxicity caused by MDMA in rats
BMC Pharmacology and Toxicology August 5, 2019 Ibrahim M. Shokry, Connor J. Shields, John J. Callanan et al.
MDMA can cause serotonin syndrome shortly after administration and serotonergic injury days or weeks later, but these two adverse effects do not always occur together, suggesting different underlying mechanisms. In rats, both a high dose (10 mg/kg three times at 2-hour intervals) and a low dose (2 mg/kg three times) increased extracellular serotonin enough to trigger serotonin syndrome of equal intensity. Modifying the environment intensified the syndrome without further raising serotonin levels. Only the high dose, which produced high MDMA concentrations in the brain, caused serotonergic injury. The findings indicate that extracellular serotonin initiates the syndrome, while postsynaptic receptor activity drives its intensification. Brain MDMA concentration determines injury initiation, and reactive oxygen species generation influences injury intensification.