Differential role of dose and environment in initiating and intensifying neurotoxicity caused by MDMA in rats

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.

Study at a glance

Abstract

Background MDMA causes serotonin (5-HT) syndrome immediately after administration and serotonergic injury in a few days or weeks. However, a serotonin syndrome is not always followed by serotonergic injury, indicating different mechanisms responsible for two adverse effects. The goal of present study was to determine causes for two adverse events and further test that dose and environment have a differential role in initiating and intensifying MDMA neurotoxicity. Methods Initiation and intensification were examined by comparing neurotoxic effects of a high-dose (10 mg/kg × 3 at 2 h intervals) with a low-dose (2 mg/kg × 3) under controlled-environmental conditions. Initiation of a serotonin syndrome was estimated by measuring extracellular 5-HT, body-core temperature, electroencephalogram and MDMA concentrations in the cerebrospinal fluid, while intensification determined in rats examined under modified environment. Initiation and intensification of the serotonergic injury were assessed in rats by measuring tissue 5-HT content, SERT density and functional integrity of serotonergic retrograde transportation. Results Both low- and high-dose could cause increases in extracellular 5-HT to elicit a serotonin syndrome at the same intensity. Modification of environmental conditions, which had no impact on MDMA-elicited increases in 5-HT levels, markedly intensified the syndrome intensity. Although either dose would cause the severe syndrome under modified environments, only the high-dose that resulted in high MDMA concentrations in the brain could cause serotonergic injury. Conclusion Our results reveal that extracellular 5-HT is the cause of a syndrome and activity of postsynaptic receptors critical for the course of syndrome intensification. Although the high-dose has the potential to initiate serotonergic injury due to high MDMA concentrations present in the brain, whether an injury is observed depends upon the drug environment via the levels of reactive oxygen species generated. This suggests that brain MDMA concentration is the determinant in the injury initiation while reactive oxygen species generation associated with the injury intensification. It is concluded that the two adverse events utilize distinctly different mediating molecules during the toxic initiation and intensification.