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A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
Chronic methamphetamine treatment reduces the expression of synaptic plasticity genes and changes their DNA
Min-Chih Cheng1, Shih-Hsin Hsu2, Chia-Hsiang Chen3
1Department 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.
Abstract:
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.
Insights
Chronic methamphetamine (METH) exposure downregulates key synaptic plasticity genes, including immediate early genes (IEGs), in mouse brain regions. DNA methylation changes in these IEGs suggest epigenetic mechanisms contribute to METH addiction.
Area of Science:
- Neuroscience
- Molecular Biology
- Epigenetics
Background:
- Methamphetamine (METH) is a psychostimulant linked to synaptic dysfunction and altered gene expression.
- Understanding molecular changes in the brain is crucial for addressing METH addiction.
Purpose of the Study:
- To investigate differential expression of synaptic plasticity genes in chronic METH-exposed mouse brains.
- To explore DNA methylation changes in immediate early genes (IEGs) associated with METH treatment.
Main Methods:
- RT(2) Profiler PCR Array and real-time quantitative PCR for gene expression analysis.
- Pyrosequencing to assess DNA methylation in CpG regions of selected IEGs.
Main Results:
- Chronic METH exposure downregulated four key IEGs (Arc, Egr2, Fos, Nr4a1) and Grm1 in the frontal cortex and hippocampus.
- Significant DNA methylation changes were observed in Arc and Fos (frontal cortex) and klf10 and Nr4a1 (hippocampus).
Conclusions:
- Chronic METH administration downregulates IEG expression in the mouse brain, potentially explaining its molecular action.
- Epigenetic regulation via DNA methylation of IEGs may play a role in METH addiction, warranting further investigation.
