C-fos, fos-B, c-jun and dusp-1 expression in the mouse heart after single and repeated methamphetamine administration

In forensic autopsy, there are numerous sudden methamphetamine (MA)-related deaths. The concentration of MA in the blood is measured to determine the cause of death in case of MA-related death. As a low concentration of MA is detected in MA-related death cases, it is sometimes difficult to identify to the cause of death. MA abusers often exhibit various cardiovascular diseases. MA induces arrhythmia and morphological change in cultured cardiomyocytes. Therefore, MA might affect heart cells, especially in terms of gene expression. Immediate early genes (IEGs) are expressed before some specific gene expressions following certain stimuli. We investigated the expression of IEGs, including c-fos, fos-B, c-jun and dusp-1 mRNA, in the mouse heart after a once-daily MA injection for 1day, 2 or 4weeks using real-time quantitative PCR. We showed that high-dose (10mg/kg) MA administration on day 1 induced mRNA expression of the four IEGs. In contrast, low-dose (1mg/kg) administration on day 1 did not induce any c-fos expression. These findings were characteristic only of the heart, since c-fos increased after treatment at any dose in the brain, suggesting that the intracellular signal cascade differs in these two organs. Nevertheless, we confirmed the transcriptional tolerance in the heart as well as the brain on chronic administration by investigating IEG expression. We were unable to explain why the expressions of IEGs were similar between both doses of MA after chronic administration, although these differed after the single treatment. Additionally, these results strongly suggest that the transcriptome must be altered after long-term treatment. As MA abuse results in various cardiovascular diseases, investigation of the transcriptome in the heart after chronic MA administration will aid in elucidating the patho-physiology of MA-related cardiovascular disease.