BioProject

MDMA (ecstasy) is an illicit drug that stimulates monoamine neurotransmitter release and inhibits reuptake. More...

MDMA (ecstasy) is an illicit drug that stimulates monoamine neurotransmitter release and inhibits reuptake. MDMA’s acute cardiotoxicity includes tachycardia and arrhythmia which are associated with cardiomyopathy (CM). MDMA acute cardiotoxicity has been explored, but neither long-term MDMA cardiac pathological changes nor epigenetic changes have been evaluated. Microarray analyses were employed to identify cardiac gene expression changes and epigenetic DNA methylation changes. To identify permanent MDMA-induced pathogenetic changes, mice received daily 10d or 35d MDMA , or daily 10d MDMA followed by 25d saline washout (10+25d). MDMA treatment (10d) caused differentially gene expression (p<0.05, fold change >1.5), with 752 genes 558 genes following 35d MDMA, and 113 genes following 10d treatment +25d washout. Changes in MAPK and circadian rhythm gene expression were identified following 10d administration. After 35d, circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) remained differentially expressed. MDMA caused DNA hypermethylation and hypomethylation that was independent of gene expression; hypermethylation of genes was 71% at 10d, 68% at 35d, and 91% at 10+25d. Differential gene expression that corresponded directly with DNA methylation changes occurred in 22% of genes at 10d, 17% at 35d, and 48% at 10d+25d washout. MDMA treatment resulted in epigenetic changes in cardiac DNA methylation. Hypermethylation was the predominant effect. MDMA induced gene expression of key elements of circadian rhythm regulatory genes and suggest a fundamental mechanism for MDMA dysfunction in the heart. This study addresses how MDMA (ecstasy) affects cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation. Overall design: Each sample was fluorescently labeled and hybridized to Roche Nimblegen 2.1M Deluxe Promoter Arrays. Less...