Prior exposure to chronic unpredictable stress (CUS) in rats amplifies the hyperthermia, corticosterone (CORT) secretion, and long-term depletion of serotonin (5-HT) in striatum, hippocampus, and frontal cortex and dopamine (DA) in striatum caused by the psychostimulant MDMA. Lowering ambient temperature to 21°C prevented these augmented effects in stressed rats, reducing them to levels seen in nonstressed, MDMA-treated animals. Blocking CORT secretion with metyrapone did not alter the monoamine depletions, indicating that the stress-induced enhancement of MDMA neurotoxicity is mediated by hyperthermia rather than by CORT itself.
MDMA, a substituted amphetamine and recreational drug, can produce mood-enhancing short-term effects that may lead to its use under stress. Clinical studies suggest MDMA treatment might alleviate symptoms of stress disorders like PTSD, but repeated use causes lasting deficits in serotonergic nerve terminal markers, indicating possible neurotoxicity. Chronic stress worsens MDMA-induced serotonergic neurotoxicity. In rats, MDMA altered gene expression in the hippocampus related to protein folding and neuropeptide signaling. In stressed rats, MDMA changed genetic responses affecting sensory processing and tissue damage responses, and reversed stress-induced downregulation of circadian rhythm genes. These transcriptional changes accompany the drug's persistent effects on neuronal structure and function.