Methamphetamine causes differential alterations in gene expression and patterns of histone acetylation/hypoacetylation in the rat nucleus accumbens
Methamphetamine (METH) addiction is associated with several neuropsychiatric symptoms. Little is known about the effects of METH on gene expression and epigenetic modifications in the rat nucleus accumbens (NAC). Our study investigated the effects of a non-toxic METH injection (20 mg/kg) on gene exp...
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| Veröffentlicht in: | PloS one 2012-03, Vol.7 (3), p.e34236 |
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| description | Methamphetamine (METH) addiction is associated with several neuropsychiatric symptoms. Little is known about the effects of METH on gene expression and epigenetic modifications in the rat nucleus accumbens (NAC). Our study investigated the effects of a non-toxic METH injection (20 mg/kg) on gene expression, histone acetylation, and the expression of the histone acetyltransferase (HAT), ATF2, and of the histone deacetylases (HDACs), HDAC1 and HDAC2, in that structure. Microarray analyses done at 1, 8, 16 and 24 hrs after the METH injection identified METH-induced changes in the expression of genes previously implicated in the acute and longterm effects of psychostimulants, including immediate early genes and corticotropin-releasing factor (Crf). In contrast, the METH injection caused time-dependent decreases in the expression of other genes including Npas4 and cholecystokinin (Cck). Pathway analyses showed that genes with altered expression participated in behavioral performance, cell-to-cell signaling, and regulation of gene expression. PCR analyses confirmed the changes in the expression of c-fos, fosB, Crf, Cck, and Npas4 transcripts. To determine if the METH injection caused post-translational changes in histone markers, we used western blot analyses and identified METH-mediated decreases in histone H3 acetylated at lysine 9 (H3K9ac) and lysine 18 (H3K18ac) in nuclear sub-fractions. In contrast, the METH injection caused time-dependent increases in acetylated H4K5 and H4K8. The changes in histone acetylation were accompanied by decreased expression of HDAC1 but increased expression of HDAC2 protein levels. The histone acetyltransferase, ATF2, showed significant METH-induced increased in protein expression. These results suggest that METH-induced alterations in global gene expression seen in rat NAC might be related, in part, to METH-induced changes in histone acetylation secondary to changes in HAT and HDAC expression. The causal role that HATs and HDACs might play in METH-induced gene expression needs to be investigated further. |
| doi_str_mv | 10.1371/journal.pone.0034236 |
| format | Article |
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Little is known about the effects of METH on gene expression and epigenetic modifications in the rat nucleus accumbens (NAC). Our study investigated the effects of a non-toxic METH injection (20 mg/kg) on gene expression, histone acetylation, and the expression of the histone acetyltransferase (HAT), ATF2, and of the histone deacetylases (HDACs), HDAC1 and HDAC2, in that structure. Microarray analyses done at 1, 8, 16 and 24 hrs after the METH injection identified METH-induced changes in the expression of genes previously implicated in the acute and longterm effects of psychostimulants, including immediate early genes and corticotropin-releasing factor (Crf). In contrast, the METH injection caused time-dependent decreases in the expression of other genes including Npas4 and cholecystokinin (Cck). Pathway analyses showed that genes with altered expression participated in behavioral performance, cell-to-cell signaling, and regulation of gene expression. PCR analyses confirmed the changes in the expression of c-fos, fosB, Crf, Cck, and Npas4 transcripts. To determine if the METH injection caused post-translational changes in histone markers, we used western blot analyses and identified METH-mediated decreases in histone H3 acetylated at lysine 9 (H3K9ac) and lysine 18 (H3K18ac) in nuclear sub-fractions. In contrast, the METH injection caused time-dependent increases in acetylated H4K5 and H4K8. The changes in histone acetylation were accompanied by decreased expression of HDAC1 but increased expression of HDAC2 protein levels. The histone acetyltransferase, ATF2, showed significant METH-induced increased in protein expression. These results suggest that METH-induced alterations in global gene expression seen in rat NAC might be related, in part, to METH-induced changes in histone acetylation secondary to changes in HAT and HDAC expression. The causal role that HATs and HDACs might play in METH-induced gene expression needs to be investigated further.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0034236</identifier><identifier>PMID: 22470541</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetylation ; Acetylation - drug effects ; Activating Transcription Factor 2 - metabolism ; Addictions ; Animals ; Biology ; Brain research ; c-Fos protein ; Central Nervous System Stimulants - pharmacology ; Cholecystokinin ; Chromatin ; Corticotropin-releasing hormone ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA microarrays ; Dopamine ; Drug abuse ; Drug dosages ; Epigenesis, Genetic - drug effects ; Epigenetic inheritance ; Epigenetics ; FosB protein ; Gene expression ; Gene Expression Regulation - drug effects ; Genes ; Genomics ; HDAC2 protein ; Histone acetyltransferase ; Histone deacetylase ; Histone Deacetylase 1 - genetics ; Histone Deacetylase 1 - metabolism ; Histone Deacetylase 2 - genetics ; Histone Deacetylase 2 - metabolism ; Histone H3 ; Histones ; Histones - genetics ; Histones - metabolism ; Immediate-early proteins ; Injection ; Lysine ; Male ; Methamphetamine ; Methamphetamine - pharmacology ; Nervous system ; Neuropeptides ; Nuclei ; Nucleus accumbens ; Nucleus Accumbens - drug effects ; Oligonucleotide Array Sequence Analysis ; Outerwear ; Post-translation ; Psychopharmacology ; Rats ; Rats, Sprague-Dawley ; Recruitment ; Rodents ; Signaling ; Systems development ; Time dependence ; Transcription factors</subject><ispartof>PloS one, 2012-03, Vol.7 (3), p.e34236</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-8b197c60502c2ba8265d2949152c5f7ec3c661b2bb4df755c7d849278f4042b3</citedby><cites>FETCH-LOGICAL-c691t-8b197c60502c2ba8265d2949152c5f7ec3c661b2bb4df755c7d849278f4042b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314616/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314616/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22470541$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martin, Tracey A</creatorcontrib><creatorcontrib>Jayanthi, Subramaniam</creatorcontrib><creatorcontrib>McCoy, Michael T</creatorcontrib><creatorcontrib>Brannock, Christie</creatorcontrib><creatorcontrib>Ladenheim, Bruce</creatorcontrib><creatorcontrib>Garrett, Tiffany</creatorcontrib><creatorcontrib>Lehrmann, Elin</creatorcontrib><creatorcontrib>Becker, Kevin G</creatorcontrib><creatorcontrib>Cadet, Jean Lud</creatorcontrib><title>Methamphetamine causes differential alterations in gene expression and patterns of histone acetylation/hypoacetylation in the rat nucleus accumbens</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Methamphetamine (METH) addiction is associated with several neuropsychiatric symptoms. Little is known about the effects of METH on gene expression and epigenetic modifications in the rat nucleus accumbens (NAC). Our study investigated the effects of a non-toxic METH injection (20 mg/kg) on gene expression, histone acetylation, and the expression of the histone acetyltransferase (HAT), ATF2, and of the histone deacetylases (HDACs), HDAC1 and HDAC2, in that structure. Microarray analyses done at 1, 8, 16 and 24 hrs after the METH injection identified METH-induced changes in the expression of genes previously implicated in the acute and longterm effects of psychostimulants, including immediate early genes and corticotropin-releasing factor (Crf). In contrast, the METH injection caused time-dependent decreases in the expression of other genes including Npas4 and cholecystokinin (Cck). Pathway analyses showed that genes with altered expression participated in behavioral performance, cell-to-cell signaling, and regulation of gene expression. PCR analyses confirmed the changes in the expression of c-fos, fosB, Crf, Cck, and Npas4 transcripts. To determine if the METH injection caused post-translational changes in histone markers, we used western blot analyses and identified METH-mediated decreases in histone H3 acetylated at lysine 9 (H3K9ac) and lysine 18 (H3K18ac) in nuclear sub-fractions. In contrast, the METH injection caused time-dependent increases in acetylated H4K5 and H4K8. The changes in histone acetylation were accompanied by decreased expression of HDAC1 but increased expression of HDAC2 protein levels. The histone acetyltransferase, ATF2, showed significant METH-induced increased in protein expression. These results suggest that METH-induced alterations in global gene expression seen in rat NAC might be related, in part, to METH-induced changes in histone acetylation secondary to changes in HAT and HDAC expression. The causal role that HATs and HDACs might play in METH-induced gene expression needs to be investigated further.</description><subject>Acetylation</subject><subject>Acetylation - drug effects</subject><subject>Activating Transcription Factor 2 - metabolism</subject><subject>Addictions</subject><subject>Animals</subject><subject>Biology</subject><subject>Brain research</subject><subject>c-Fos protein</subject><subject>Central Nervous System Stimulants - pharmacology</subject><subject>Cholecystokinin</subject><subject>Chromatin</subject><subject>Corticotropin-releasing hormone</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA microarrays</subject><subject>Dopamine</subject><subject>Drug abuse</subject><subject>Drug dosages</subject><subject>Epigenesis, Genetic - drug effects</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>FosB protein</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Genes</subject><subject>Genomics</subject><subject>HDAC2 protein</subject><subject>Histone acetyltransferase</subject><subject>Histone deacetylase</subject><subject>Histone Deacetylase 1 - genetics</subject><subject>Histone Deacetylase 1 - metabolism</subject><subject>Histone Deacetylase 2 - genetics</subject><subject>Histone Deacetylase 2 - metabolism</subject><subject>Histone H3</subject><subject>Histones</subject><subject>Histones - genetics</subject><subject>Histones - metabolism</subject><subject>Immediate-early proteins</subject><subject>Injection</subject><subject>Lysine</subject><subject>Male</subject><subject>Methamphetamine</subject><subject>Methamphetamine - pharmacology</subject><subject>Nervous system</subject><subject>Neuropeptides</subject><subject>Nuclei</subject><subject>Nucleus accumbens</subject><subject>Nucleus Accumbens - drug effects</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Outerwear</subject><subject>Post-translation</subject><subject>Psychopharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Recruitment</subject><subject>Rodents</subject><subject>Signaling</subject><subject>Systems development</subject><subject>Time dependence</subject><subject>Transcription 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advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martin, Tracey A</au><au>Jayanthi, Subramaniam</au><au>McCoy, Michael T</au><au>Brannock, Christie</au><au>Ladenheim, Bruce</au><au>Garrett, Tiffany</au><au>Lehrmann, Elin</au><au>Becker, Kevin G</au><au>Cadet, Jean Lud</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Methamphetamine causes differential alterations in gene expression and patterns of histone acetylation/hypoacetylation in the rat nucleus accumbens</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-03-28</date><risdate>2012</risdate><volume>7</volume><issue>3</issue><spage>e34236</spage><pages>e34236-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Methamphetamine (METH) addiction is associated with several neuropsychiatric symptoms. Little is known about the effects of METH on gene expression and epigenetic modifications in the rat nucleus accumbens (NAC). Our study investigated the effects of a non-toxic METH injection (20 mg/kg) on gene expression, histone acetylation, and the expression of the histone acetyltransferase (HAT), ATF2, and of the histone deacetylases (HDACs), HDAC1 and HDAC2, in that structure. Microarray analyses done at 1, 8, 16 and 24 hrs after the METH injection identified METH-induced changes in the expression of genes previously implicated in the acute and longterm effects of psychostimulants, including immediate early genes and corticotropin-releasing factor (Crf). In contrast, the METH injection caused time-dependent decreases in the expression of other genes including Npas4 and cholecystokinin (Cck). Pathway analyses showed that genes with altered expression participated in behavioral performance, cell-to-cell signaling, and regulation of gene expression. PCR analyses confirmed the changes in the expression of c-fos, fosB, Crf, Cck, and Npas4 transcripts. To determine if the METH injection caused post-translational changes in histone markers, we used western blot analyses and identified METH-mediated decreases in histone H3 acetylated at lysine 9 (H3K9ac) and lysine 18 (H3K18ac) in nuclear sub-fractions. In contrast, the METH injection caused time-dependent increases in acetylated H4K5 and H4K8. The changes in histone acetylation were accompanied by decreased expression of HDAC1 but increased expression of HDAC2 protein levels. The histone acetyltransferase, ATF2, showed significant METH-induced increased in protein expression. These results suggest that METH-induced alterations in global gene expression seen in rat NAC might be related, in part, to METH-induced changes in histone acetylation secondary to changes in HAT and HDAC expression. The causal role that HATs and HDACs might play in METH-induced gene expression needs to be investigated further.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22470541</pmid><doi>10.1371/journal.pone.0034236</doi><tpages>e34236</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-03, Vol.7 (3), p.e34236 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1325007688 |
| source | PLoS; MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Acetylation Acetylation - drug effects Activating Transcription Factor 2 - metabolism Addictions Animals Biology Brain research c-Fos protein Central Nervous System Stimulants - pharmacology Cholecystokinin Chromatin Corticotropin-releasing hormone Deoxyribonucleic acid DNA DNA methylation DNA microarrays Dopamine Drug abuse Drug dosages Epigenesis, Genetic - drug effects Epigenetic inheritance Epigenetics FosB protein Gene expression Gene Expression Regulation - drug effects Genes Genomics HDAC2 protein Histone acetyltransferase Histone deacetylase Histone Deacetylase 1 - genetics Histone Deacetylase 1 - metabolism Histone Deacetylase 2 - genetics Histone Deacetylase 2 - metabolism Histone H3 Histones Histones - genetics Histones - metabolism Immediate-early proteins Injection Lysine Male Methamphetamine Methamphetamine - pharmacology Nervous system Neuropeptides Nuclei Nucleus accumbens Nucleus Accumbens - drug effects Oligonucleotide Array Sequence Analysis Outerwear Post-translation Psychopharmacology Rats Rats, Sprague-Dawley Recruitment Rodents Signaling Systems development Time dependence Transcription factors |
| title | Methamphetamine causes differential alterations in gene expression and patterns of histone acetylation/hypoacetylation in the rat nucleus accumbens |
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