Effects of Stress and MDMA on Hippocampal Gene Expression

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.

Study at a glance

Abstract

MDMA (3,4-methylenedioxymethamphetamine) is a substituted amphetamine and popular drug of abuse. Its mood-enhancing short-term effects may prompt its consumption under stress. Clinical studies indicate that MDMA treatment may mitigate the symptoms of stress disorders such as posttraumatic stress syndrome (PTSD). On the other hand, repeated administration of MDMA results in persistent deficits in markers of serotonergic (5-HT) nerve terminals that have been viewed as indicative of 5-HT neurotoxicity. Exposure to chronic stress has been shown to augment MDMA-induced 5-HT neurotoxicity. Here, we examine the transcriptional responses in the hippocampus to MDMA treatment of control rats and rats exposed to chronic stress. MDMA altered the expression of genes that regulate unfolded protein binding, protein folding, calmodulin-dependent protein kinase activity, and neuropeptide signaling. In stressed rats, the gene expression profile in response to MDMA was altered to affect sensory processing and responses to tissue damage in nerve sheaths. Subsequent treatment with MDMA also markedly altered the genetic responses to stress such that the stress-induced downregulation of genes related to the circadian rhythm was reversed. The data support the view that MDMA-induced transcriptional responses accompany the persistent effects of this drug on neuronal structure/function. In addition, MDMA treatment alters the stress-induced transcriptional signature.