Chronic methamphetamine treatment reduces the expression of synaptic plasticity genes and changes their DNA methylation status in the mouse brain.
Methamphetamine (METH) is a highly addictive psychostimulant that may cause long-lasting synaptic dysfunction and abnormal gene expression. We aimed to explore the differential expression of synaptic plasticity genes in chronic METH-treated mouse brain. We used the RT(2) Profiler PCR Array and the real-time quantitative PCR to characterize differentially expressed synaptic plasticity genes in the frontal cortex and the hippocampus of chronic METH-treated mice compared with normal saline-treated mice. We further used pyrosequencing to assess DNA methylation changes in the CpG region of the five immediate early genes (IEGs) in chronic METH-treated mouse brain. We detected six downregulated genes in the frontal cortex and the hippocampus of chronic METH-treated mice, including five IEGs (Arc, Egr2, Fos, Klf10, and Nr4a1) and one neuronal receptor gene (Grm1), compared with normal saline-treated group, but only four genes (Arc, Egr2, Fos, and Nr4a1) were confirmed to be different. Furthermore, we found several CpG sites of the Arc and the Fos that had significant changes in DNA methylation status in the frontal cortex of chronic METH-treated mice, while the klf10 and the Nr4a1 that had significant changes in the hippocampus. Our results show that chronic administration of METH may lead to significant downregulation of the IEGs expression in both the frontal cortex and the hippocampus, which may partly account for the molecular mechanism of the action of METH. Furthermore, the changes in DNA methylation status of the IEGs in the brain indicate that an epigenetic mechanism-dependent transcriptional regulation may contribute to METH addiction, which warrants additional study.
Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan; Center for General Education, St. Mary׳s Junior College of Medicine, Nursing and Management, Yilan County, Taiwan. Electronic address: cmc@mail.vhyl.gov.tw.
Min-Chih
MC
Cheng
Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
Shih-Hsin
SH
Hsu
Department of Psychiatry, Chang Gung Memorial Hospital at Linkou and Department and Graduate school of Biomedical Sciences Chang Gung University, Taoyuan, Taiwan.
Chia-Hsiang
CH
Chen
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*
D008694:Methamphetamine
DNA methylation; Gene expression; Immediate early gene; Methamphetamine; Synaptic plasticity