The effect of chronic stress on (+)3,4-methylenedioxymethamphetamine (MDMA) neurotoxicity

Chronic stress precipitates psychostimulant abuse and enhances the acute physiological and behavioral effects of psychostimulants; however the effects of chronic stress on psychostimulant neurotoxicity are unknown. Therefore, this research determined how chronic stress impacts the acute physiological effects of the psychostimulant 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) to enhance long-term neurotoxicity in the rat brain. To determine mechanisms by which chronic stress could produce neuronal sensitivity to MDMA, the effects of chronic stress on inflammatory mediators and serotonin transporter immunoreactivity were investigated. Chronic stress increased plasma corticosterone and interleukin-1beta as well as hippocampal interleukin-1a and interleukin-1 receptor 1 immunoreactivity but had no effect on serotonin transporter immunoreactivity. These chronic stress-induced increases in corticosterone and inflammatory markers were accompanied by an augmentation in hyperthermia, corticosterone, and hippocampal interleukin-1beta and inducible nitric oxide synthase expression in response to MDMA after chronic stress. The combination of chronic stress and MDMA exacerbated long-term serotonin tissue content depletions in the striatum, hippocampus, and frontal cortex. Moreover, MDMA caused an uncharacteristic dopamine depletion in the striatum but not in the cortex of stressed compared to non-stressed rats. The increases in corticosterone and inflammation associated with chronic stress were necessary for the enhancement of the hyperthermic response and neurotoxicity to MDMA after chronic stress. The roles of hyperthermia and corticosterone in mediating the enhanced neurotoxicity to MDMA after chronic stress were investigated. The augmented hyperthermic response to MDMA after chronic stress was found to mediate the enhancements in corticosterone, interleukin-1beta, and inducible nitric oxide synthase as well as the exacerbated serotonin and dopamine depletions after chronic stress and MDMA. Corticosterone in response to MDMA was not involved in serotonin or dopamine depletions regardless of stress exposure. These studies demonstrate that increases in corticosterone and inflammation associated with chronic stress render serotonin as well as dopamine terminals vulnerable to the neurotoxic effects of MDMA. Additionally, the enhancement in MDMA-induced hyperthermia exhibited by chronically stressed rats mediates the exacerbation of MDMA neurotoxicity as well as the neuro-inflammatory response to MDMA after chronic stress. Overall, these studies illustrate a mechanism by which inflammation and hyperthermia contribute to chronic stress-induced increases in MDMA neurotoxicity.