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

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. Electronic supplementary material The online version of this article (10.1186/s40360-019-0326-6) contains supplementary material, which is available to authorized users.

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…3,4-Methylenedioxymethamphetamine Neurotoxicity. Several studies have investigated whether MDMA is neurotoxic on neurotransmitter systems (Schmidt, 1987;Gudelsky et al, 1994;Armstrong and Noguchi, 2004;Granado et al, 2011;Shokry et al, 2019) given that this compound is also used to induce dopaminergic toxicity in mouse models (Blesa and Przedborski, 2014). Catechols derived from MDMA metabolism appear to be responsible for the neurotoxic effects of MDMA given that direct intracerebroventricular administration of MDMA does not elicit 5-HT neurotoxicity (Green et al, 2003).…”

Activation of Antioxidant and Proteolytic Pathways in the Nigrostriatal Dopaminergic System After 3,4-Methylenedioxymethamphetamine Administration: Sex-Related Differences

“…It has been previously proposed that hyperthermia induced by amphetamine-related drugs may increase the formation of ROS and reactive nitrogen species (Chipana et al, 2008;Sharma and Ali, 2008;Shokry et al, 2019). However, other studies have demonstrated that MDMA may increase the levels of oxidative stress by mechanisms other than the induction of hyperthermia (Jayanthi et al, 1999;Peraile et al, 2013).…”

“…Previous studies from our and other laboratories have suggested that hyperthermia, which is a commonly observed noxious effect of MDMA (Green et al, 2003;Hall and Henry, 2006), may favor the neurotoxicity and/or glia activation induced by this amphetamine-related drug (Miller and O'Callaghan, 1995;Colado et al, 1998;Mechan et al, 2001;Touriño et al, 2010;Frau et al, 2013), with a mechanism that is thought to stem from increased production and release of reactive oxygen species (ROS) (Chipana et al, 2008;Sharma and Ali, 2008;Shokry et al, 2019). However, other authors have demonstrated that MDMA can induce the release of ROS and neurotoxicity in experimental animals by means of mechanisms that are independent of hyperthermia (Green et al, 2004).…”