{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:47:40Z","timestamp":1789152460147,"version":"build-2803163510"},"reference-count":72,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T00:00:00Z","timestamp":1623369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health (NIH)\/National Institute of Drug Abuse","award":["R01 DA044872"],"award-info":[{"award-number":["R01 DA044872"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Illicit drugs are known to affect central nervous system (CNS). Majorly psychostimulants such as cocaine, methamphetamine (METH) and opioids such as morphine are known to induce epigenetic changes of histone modifications and chromatin remodeling which are mediated by histone acetyltransferase (HAT) and histone deacetylase (HDAC). Aberrant changes in histone acetylation-deacetylation process further exacerbate dysregulation of gene expression and protein modification which has been linked with neuronal impairments including memory formation and synaptic plasticity. In CNS, astrocytes play a pivotal role in cellular homeostasis. However, the impact of psychostimulants and opioid mediated epigenetic changes of HAT\/HADCs in astrocytes has not yet been fully elucidated. Therefore, we have investigated the effects of the psychostimulants and opioid on the acetylation-regulating enzymes- HAT and HDACs role in astrocytes. In this study, Class I and II HDACs and HATs gene expression, protein changes and global level changes of acetylation of H3 histones at specific lysines were analyzed. In addition, we have explored the neuroprotective \u201cnootropic\u201d drug piracetam were exposed with or without psychostimulants and opioid in the human primary astrocytes. Results revealed that psychostimulants and opioid upregulated HDAC1, HDAC4 and p300 expression, while HDAC5 and GCN5 expression were downregulated. These effects were reversed by piracetam coexposure. Psychostimulants and opioid exposure upregulated global acetylation levels of all H3Ks, except H3K14. These results suggest that psychostimulants and opioids differentially influence HATs and HDACs.<\/jats:p>","DOI":"10.1371\/journal.pone.0252895","type":"journal-article","created":{"date-parts":[[2021,6,11]],"date-time":"2021-06-11T17:28:26Z","timestamp":1623432506000},"page":"e0252895","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":35,"title":["Psychostimulants and opioids differentially influence the epigenetic modification of histone acetyltransferase and histone deacetylase in astrocytes"],"prefix":"10.1371","volume":"16","author":[{"given":"Mayur","family":"Doke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gurudutt","family":"Pendyala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5071-056X","authenticated-orcid":true,"given":"Thangavel","family":"Samikkannu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,6,11]]},"reference":[{"key":"pone.0252895.ref001","first-page":"278","volume-title":"Protein and Cell","author":"XL Hu","year":"2012"},{"key":"pone.0252895.ref002","first-page":"41","volume-title":"Nature","author":"BD Strahl","year":"2000"},{"key":"pone.0252895.ref003","first-page":"355","volume-title":"Nature Reviews Neuroscience","author":"N Tsankova","year":"2007"},{"key":"pone.0252895.ref004","first-page":"693","volume-title":"Cell","author":"T. 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Sheng","year":"2011","journal-title":"Neuroreport"},{"key":"pone.0252895.ref021","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.biopsych.2016.09.015","article-title":"Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target","volume":"81","author":"G Egervari","year":"2017","journal-title":"Biol Psychiatry"},{"key":"pone.0252895.ref022","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.brainres.2016.06.019","article-title":"Microinjection of histone deacetylase inhibitor into the ventrolateral orbital cortex potentiates morphine induced behavioral sensitization","volume":"1646","author":"L Wei","year":"2016","journal-title":"Brain Res"},{"key":"pone.0252895.ref023","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s12031-014-0317-4","article-title":"Inhibition of Histone Deacetylase in the Basolateral Amygdala Facilitates Morphine Context-Associated Memory Formation 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through PKC\u03b3 phosphorylation in mice with methamphetamine-induced place preference","volume":"118","author":"M Shibasaki","year":"2011","journal-title":"J Neurochem"},{"key":"pone.0252895.ref030","doi-asserted-by":"crossref","first-page":"3571","DOI":"10.1523\/JNEUROSCI.0037-07.2007","article-title":"Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington\u2019s disease by increasing tubulin acetylation","volume":"27","author":"JP Dompierre","year":"2007","journal-title":"J Neurosci"},{"key":"pone.0252895.ref031","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1073\/pnas.0737363100","article-title":"Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway","volume":"100","author":"H Ryu","year":"2003","journal-title":"Proc Natl Acad Sci U S 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Winblad","year":"2005"},{"key":"pone.0252895.ref035","first-page":"169","volume-title":"CNS Drug Reviews","author":"B. Winblad","year":"2005"},{"key":"pone.0252895.ref036","doi-asserted-by":"crossref","first-page":"614","DOI":"10.3389\/fmicb.2015.00614","article-title":"HIV-1 gp120 and morphine induced oxidative stress: role in cell cycle regulation","volume":"6","author":"T Samikkannu","year":"2015","journal-title":"Front Microbiol"},{"key":"pone.0252895.ref037","first-page":"1","article-title":"HIV-Tat and Cocaine Impact Brain Energy Metabolism: Redox Modification and Mitochondrial Biogenesis Influence NRF Transcription-Mediated Neurodegeneration","author":"K Sivalingam","year":"2020","journal-title":"Mol Neurobiol"},{"key":"pone.0252895.ref038","doi-asserted-by":"crossref","first-page":"611","DOI":"10.3390\/brainsci10090611","article-title":"Neuroprotective Effect of Piracetam against Cocaine-Induced Neuro Epigenetic Modification of DNA Methylation in Astrocytes","volume":"10","author":"K Sivalingam","year":"2020","journal-title":"Brain Sci"},{"key":"pone.0252895.ref039","article-title":"HIV-1 Tat 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Substrates","volume":"18","author":"W Xu","year":"1998","journal-title":"Mol Cell Biol"},{"key":"pone.0252895.ref044","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.mrfmmm.2006.09.009","article-title":"Histone modifications in response to DNA damage","volume":"618","author":"M Altaf","year":"2007","journal-title":"Mutat Res\u2014Fundam Mol Mech Mutagen"},{"key":"pone.0252895.ref045","first-page":"707","volume-title":"Cell","author":"B Li","year":"2007"},{"key":"pone.0252895.ref046","first-page":"621","volume-title":"Trends in Biochemical Sciences","author":"HM Herz","year":"2013"},{"key":"pone.0252895.ref047","first-page":"747","volume-title":"Handbook of Clinical Neurology","author":"DM Walker","year":"2018"},{"key":"pone.0252895.ref048","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S1097-2765(01)00301-X","article-title":"Highly specific antibodies determine histone acetylation site usage in yeast heterochromatin and euchromatin","volume":"8","author":"N Suka","year":"2001","journal-title":"Mol Cell"},{"key":"pone.0252895.ref049","first-page":"81","volume-title":"Annual Review of Biochemistry","author":"SY Roth","year":"2001"},{"key":"pone.0252895.ref050","first-page":"728","volume-title":"Cellular and Molecular Life Sciences","author":"S Timmermann","year":"2001"},{"key":"pone.0252895.ref051","first-page":"321","volume-title":"Hormones and Behavior","author":"Q LaPlant","year":"2011"},{"key":"pone.0252895.ref052","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.neuron.2005.09.023","article-title":"Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum","volume":"48","author":"A Kumar","year":"2005","journal-title":"Neuron"},{"key":"pone.0252895.ref053","first-page":"573","volume-title":"Expert Opinion on Investigational Drugs","author":"SF Sleiman","year":"2009"},{"key":"pone.0252895.ref054","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1038\/nn.2471","article-title":"HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage","volume":"13","author":"JY Kim","year":"2010","journal-title":"Nat Neurosci"},{"key":"pone.0252895.ref055","doi-asserted-by":"crossref","first-page":"7547","DOI":"10.1523\/JNEUROSCI.3000-16.2017","article-title":"Subcellular distribution of HDAC1 in neurotoxic conditions is dependent on serine phosphorylation","volume":"37","author":"Y Zhu","year":"2017","journal-title":"J Neurosci"},{"key":"pone.0252895.ref056","doi-asserted-by":"crossref","first-page":"17335","DOI":"10.1073\/pnas.0706487104","article-title":"Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases","volume":"104","author":"A Lahm","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0252895.ref057","doi-asserted-by":"crossref","first-page":"10879","DOI":"10.1523\/JNEUROSCI.2089-12.2012","article-title":"An essential role for histone deacetylase 4 in synaptic plasticity and memory formation","volume":"32","author":"MS Kim","year":"2012","journal-title":"J Neurosci"},{"key":"pone.0252895.ref058","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.cell.2012.09.037","article-title":"HDAC4 governs a transcriptional program essential for synaptic plasticity and memory","volume":"151","author":"R Sando","year":"2012","journal-title":"Cell"},{"key":"pone.0252895.ref059","first-page":"1","article-title":"Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription","volume":"10","author":"Y Zhu","year":"2019","journal-title":"Nat Commun"},{"key":"pone.0252895.ref060","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1111\/adb.12522","article-title":"Novel role and regulation of HDAC4 in cocaine-related behaviors","volume":"23","author":"RD Penrod","year":"2018","journal-title":"Addict Biol"},{"key":"pone.0252895.ref061","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.toxlet.2015.02.011","article-title":"Methamphetamine promotes \u03b1-tubulin deacetylation in endothelial cells: The protective role of acetyl-l-carnitine","volume":"234","author":"S Fernandes","year":"2015","journal-title":"Toxicol Lett"},{"key":"pone.0252895.ref062","doi-asserted-by":"crossref","first-page":"19599","DOI":"10.1073\/pnas.0907935106","article-title":"HDAC6 is a target for protection and regeneration following injury in the nervous system","volume":"106","author":"MA Rivieccio","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0252895.ref063","doi-asserted-by":"crossref","first-page":"9633","DOI":"10.1073\/pnas.0803749105","article-title":"HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation","volume":"105","author":"RB 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histone deacetylase HDAC5","volume":"66","author":"JB Dietrich","year":"2012","journal-title":"Synapse"},{"key":"pone.0252895.ref068","first-page":"94","volume-title":"Neuropsychopharmacology","author":"GA Rogge","year":"2013"},{"key":"pone.0252895.ref069","doi-asserted-by":"crossref","first-page":"19186","DOI":"10.1073\/pnas.0509735102","article-title":"CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum","volume":"102","author":"AA Levine","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0252895.ref070","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.neuron.2004.05.021","article-title":"Chromatin acetylation, memory, and LTP are impaired in CBP+\/- mice: A model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration","volume":"42","author":"JM 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