Abstract
BackgroundMethamphetamine (METH) is one of the most widely abused illicit substances worldwide; unfortunately, its addiction mechanism remains unclear. Based on accumulating evidence, changes in gene expression and chromatin modifications might be related to the persistent effects of METH on the brain. In the present study, we took advantage of METH-induced behavioral sensitization as an animal model that reflects some aspects of drug addiction and examined the changes in gene expression and histone acetylation in the prefrontal cortex (PFC) of adult rats.MethodsWe conducted mRNA microarray and chromatin immunoprecipitation (ChIP) coupled to DNA microarray (ChIP-chip) analyses to screen and identify changes in transcript levels and histone acetylation patterns. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were performed to analyze the differentially expressed genes. We then further identified alterations in ANP32A (acidic leucine-rich nuclear phosphoprotein-32A) and POU3F2 (POU domain, class 3, transcription factor 2) using qPCR and ChIP-PCR assays.ResultsIn the rat model of METH-induced behavioral sensitization, METH challenge caused 275 differentially expressed genes and a number of hyperacetylated genes (821 genes with H3 acetylation and 10 genes with H4 acetylation). Based on mRNA microarray and GO and KEGG enrichment analyses, 24 genes may be involved in METH-induced behavioral sensitization, and 7 genes were confirmed using qPCR. We further examined the alterations in the levels of the ANP32A and POU3F2 transcripts and histone acetylation at different periods of METH-induced behavioral sensitization. H4 hyperacetylation contributed to the increased levels of ANP32A mRNA and H3/H4 hyperacetylation contributed to the increased levels of POU3F2 mRNA induced by METH challenge-induced behavioral sensitization, but not by acute METH exposure.ConclusionsThe present results revealed alterations in transcription and histone acetylation in the rat PFC by METH exposure and provided evidence that modifications of histone acetylation contributed to the alterations in gene expression caused by METH-induced behavioral sensitization.
Highlights
Methamphetamine (METH) is one of the most widely abused illicit substances worldwide; unfortu‐ nately, its addiction mechanism remains unclear
We focused on whether the changes in gene expression occurring in response to METH-induced behavioral sensitization are related to histone acetylation in the prefrontal cortex (PFC)
METH‐induced behavioral sensitization The model of behavioral sensitization was established by 7 days of METH (5.0 mg/kg, s.c.) administration followed by 7 days of withdrawal and challenged with a single METH injection (1.0 mg/kg, s.c.) on day 15
Summary
Methamphetamine (METH) is one of the most widely abused illicit substances worldwide; unfortu‐ nately, its addiction mechanism remains unclear. Changes in gene expression and chromatin modifications might be related to the persistent effects of METH on the brain. We took advantage of METH-induced behavioral sensitization as an animal model that reflects some aspects of drug addiction and examined the changes in gene expression and histone acetylation in the prefrontal cortex (PFC) of adult rats. The enduring effects of these drugs, even after long periods of abstinence, have suggested the presence of persistent molecular events caused by transcriptional, epigenetic and translational changes [1] within addictionrelated brain regions [2], such as the nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus. With respect to METH, only a few studies have investigated the epigenetic effects of these drugs, mainly focusing on the NAc and striatum [10,11,12,13,14]
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