{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:49:44Z","timestamp":1775090984318,"version":"3.50.1"},"reference-count":57,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T00:00:00Z","timestamp":1603756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO 2012\/06\/A\/NZ3\/00022"],"award-info":[{"award-number":["UMO 2012\/06\/A\/NZ3\/00022"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Maj Institute of Pharmacology Polish Academy of Sciences","award":["statutory funds"],"award-info":[{"award-number":["statutory funds"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cocaine induces neuronal changes as well as non-neuronal (astrocytes, microglia, oligodendroglia) mechanisms, but these changes can also be modulated by various types of drug abstinence. Due to the very complex and still incompletely understood nature of cocaine use disorder, understanding of the mechanisms involved in addictive behavior is necessary to further search for effective pharmacotherapy of this disease. The aim of this study was to investigate changes at the gene and protein levels associated with glial cell activity after cocaine exposure, as well as during early cocaine abstinence (3 days) with extinction training or in home cage isolation. Cocaine self-administration significantly decreased myelin regulatory factor (MYRF) and cyclic nucleotide phosphodiesterase (CNP) expression in the hippocampus as well as pleckstrin (PLEK) and T-lymphocyte activation antigen (CD86) in the rat striatum. Depending on cocaine abstinence conditions, microglial PLEK expression was increased through extinction training but did not change in the home cage isolation. In addition, downregulation of gene expression associated with oligodendrocytes (CNP, MYRF) and microglia regulator of G protein signaling 1 (RGS1) was observed in the hippocampus, regardless of the type of drug abstinence, while downregulation of myelin and lymphocyte protein (MAL) expression was found only in rats exposed to abstinence in the home cage. Taken together, the presented results strongly suggest that cocaine abstinence evokes significant changes in gene expression associated with the proper functioning of glial cells, suggesting their significant involvement in adaptive changes in the brain associated with cocaine exposure. Interestingly, drug abstinence conditions are important factors influencing observed changes at the transcript levels of selected genes, which may be of clinical interest.<\/jats:p>","DOI":"10.3390\/ijms21217970","type":"journal-article","created":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T09:22:45Z","timestamp":1603790565000},"page":"7970","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cocaine Administration and Its Abstinence Conditions Modulate Neuroglia"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7015-154X","authenticated-orcid":false,"given":"Kinga","family":"Gawli\u0144ska","sequence":"first","affiliation":[{"name":"Maj Institute of Pharmacology Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Sm\u0119tna 12 Street, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6646-6140","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Frankowska","sequence":"additional","affiliation":[{"name":"Maj Institute of Pharmacology Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Sm\u0119tna 12 Street, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-0564","authenticated-orcid":false,"given":"Dawid","family":"Gawli\u0144ski","sequence":"additional","affiliation":[{"name":"Maj Institute of Pharmacology Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Sm\u0119tna 12 Street, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2468-151X","authenticated-orcid":false,"given":"Marcin","family":"Piechota","sequence":"additional","affiliation":[{"name":"Maj Institute of Pharmacology Polish Academy of Sciences, Department of Molecular Neuropharmacology, Sm\u0119tna 12 Street, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Micha\u0142","family":"Korosty\u0144ski","sequence":"additional","affiliation":[{"name":"Maj Institute of Pharmacology Polish Academy of Sciences, Department of Molecular Neuropharmacology, Sm\u0119tna 12 Street, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma\u0142gorzata","family":"Filip","sequence":"additional","affiliation":[{"name":"Maj Institute of Pharmacology Polish Academy of Sciences, Department of Drug Addiction Pharmacology, Sm\u0119tna 12 Street, 31-343 Krak\u00f3w, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1111\/j.1365-2125.2012.04474.x","article-title":"Future pharmacological treatments for substance use disorders","volume":"77","author":"Forray","year":"2014","journal-title":"Br. J. Clin. Pharm."},{"key":"ref_2","first-page":"112","article-title":"Substance Misuse and Substance use Disorders: Why do they Matter in Healthcare?","volume":"128","author":"McLellan","year":"2017","journal-title":"Trans. Am. Clin. Clim. Assoc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"581","DOI":"10.3389\/fncel.2019.00581","article-title":"Cocaine Self-administration and Extinction Inversely Alter Neuron to Glia Exosomal Dynamics in the Nucleus Accumbens","volume":"13","author":"Jarvis","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_4","unstructured":"(2020, September 01). A World Drug Report. Available online: https:\/\/wdr.unodc.org\/wdr2020\/."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.biopsych.2018.04.009","article-title":"Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain\u2019s Reward Circuitry","volume":"84","author":"Walker","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.nbd.2018.05.017","article-title":"Cocaine-mediated activation of microglia and microglial MeCP2 and BDNF production","volume":"117","author":"Cotto","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"335","DOI":"10.31887\/DCNS.2014.16.3\/pkenny","article-title":"Epigenetics, microRNA, and addiction","volume":"16","author":"Kenny","year":"2014","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"76","DOI":"10.2174\/1874473710902010076","article-title":"The Role of Glial Cells in Drug Abuse","volume":"2","year":"2009","journal-title":"Curr. Drug Abus. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1017\/S1461145706007322","article-title":"Oligodendroglial abnormalities in schizophrenia, mood disorders and substance abuse. Comorbidity, shared traits, or molecular phenocopies?","volume":"10","author":"Sokolov","year":"2007","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.tips.2006.01.005","article-title":"Historical review: ATP as a neurotransmitter","volume":"27","author":"Burnstock","year":"2006","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1523\/JNEUROSCI.20-01-00251.2000","article-title":"AMPA-kainate subtypes of glutamate receptor in rat cerebral microglia","volume":"20","author":"Noda","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3196","DOI":"10.1007\/s12035-017-0584-5","article-title":"Cocaine-Mediated Downregulation of miR-124 Activates Microglia by Targeting KLF4 and TLR4 Signaling","volume":"55","author":"Periyasamy","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.psychres.2008.10.034","article-title":"Decreased brain dopamine cell numbers in human cocaine users","volume":"168","author":"Little","year":"2009","journal-title":"Psychiatry Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8868","DOI":"10.1038\/s41598-018-27293-5","article-title":"Brain Cell Type Specific Gene Expression and Co-expression Network Architectures","volume":"8","author":"McKenzie","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/npp.2009.110","article-title":"Neurocircuitry of addiction","volume":"35","author":"Koob","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.devcel.2011.08.023","article-title":"Between the sheets: A molecular sieve makes myelin membranes","volume":"21","author":"Zuchero","year":"2011","journal-title":"Dev. Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s00401-017-1741-7","article-title":"Myelin regulatory factor drives remyelination in multiple sclerosis","volume":"134","author":"Duncan","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1126\/science.1254960","article-title":"Motor skill learning requires active central myelination","volume":"346","author":"McKenzie","year":"2014","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0301-0082(99)00039-8","article-title":"MAL, a proteolipid in glycosphingolipid enriched domains: Functional implications in myelin and beyond","volume":"60","author":"Frank","year":"2000","journal-title":"Prog. Neurobiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1038\/mp.2017.116","article-title":"The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling","volume":"23","author":"Cahill","year":"2018","journal-title":"Mol. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1177\/026988119901300211","article-title":"Impulsivity: A discussion of clinical and experimental findings","volume":"13","author":"Evenden","year":"1999","journal-title":"J. Psychopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.bbr.2019.01.022","article-title":"Differential gene expression in the mesocorticolimbic system of innately high- and low-impulsive rats","volume":"364","author":"Moloney","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s00726-006-0479-7","article-title":"Structural properties of proteins specific to the myelin sheath","volume":"34","author":"Kursula","year":"2008","journal-title":"Amino Acids"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1046\/j.1471-4159.2003.02247.x","article-title":"Gene expression profile of the nucleus accumbens of human cocaine abusers: Evidence for dysregulation of myelin","volume":"88","author":"Albertson","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1080\/13556210412331308921","article-title":"Gene expression profiling in the brains of human cocaine abusers","volume":"10","author":"Bannon","year":"2005","journal-title":"Addict. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1007\/s11064-008-9655-3","article-title":"Expression of transcripts for myelin related genes in postmortem brain from cocaine abusers","volume":"34","author":"Kristiansen","year":"2009","journal-title":"Neurochem. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1097\/01.alc.0000179406.98868.59","article-title":"Expression of MBP, PLP, MAG, CNP, and GFAP in the human alcoholic brain","volume":"29","author":"Lewohl","year":"2005","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1038\/sj.npp.1301626","article-title":"Extended access to cocaine self-administration produces long-lasting prefrontal cortex-dependent working memory impairments","volume":"33","author":"George","year":"2008","journal-title":"Neuropsychopharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1016\/j.ajpath.2012.08.013","article-title":"Cocaine-induced loss of white matter proteins in the adult mouse nucleus accumbens is attenuated by administration of a \u03b2-lactam antibiotic during cocaine withdrawal","volume":"181","author":"Kovalevich","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8131","DOI":"10.1073\/pnas.0702157104","article-title":"Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders","volume":"104","author":"Roy","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/hipo.22183","article-title":"Hippocampus and striatum: Dynamics and interaction during acquisition and sleep-related motor sequence memory consolidation","volume":"23","author":"Albouy","year":"2013","journal-title":"Hippocampus"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1162\/jocn.1995.7.4.497","article-title":"Functional mapping of sequence learning in normal humans","volume":"7","author":"Grafton","year":"1995","journal-title":"J. Cogn. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/sj.mp.4001424","article-title":"Sequence? What Sequence?: The human medial temporal lobe and sequence learning","volume":"8","author":"Schendan","year":"2003","journal-title":"Mol. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/BF00419678","article-title":"Effects of aging on implicit sequence learning: Accounting for sequence structure and explicit knowledge","volume":"60","author":"Curran","year":"1997","journal-title":"Psychol. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/brain\/124.1.67","article-title":"Characterizing the neural mechanisms of skill learning and repetition priming evidence from mirror reading","volume":"124","author":"Poldrack","year":"2001","journal-title":"Brain"},{"key":"ref_36","first-page":"100169","article-title":"Learning functions in short-term cocaine users","volume":"9","author":"Kumar","year":"2019","journal-title":"Addict. Behav. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1002\/jnr.10245","article-title":"Oligodendrocytes as providers of growth factors","volume":"68","author":"Du","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3109\/15622975.2013.829585","article-title":"Glial abnormalities in substance use disorders and depression: Does shared glutamatergic dysfunction contribute to comorbidity?","volume":"15","author":"Niciu","year":"2014","journal-title":"World J. Biol. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1080\/15548627.2015.1052205","article-title":"Cocaine-mediated microglial activation involves the ER stress-autophagy axis","volume":"11","author":"Guo","year":"2015","journal-title":"Autophagy"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1515\/REVNEURO.2002.13.3.221","article-title":"Reciprocal interactions between microglia and neurons: From survival to neuropathology","volume":"13","author":"Polazzi","year":"2002","journal-title":"Rev. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1128\/CDLI.7.5.719-723.2000","article-title":"Detection and function of opioid receptors on cells from the immune system","volume":"7","author":"Bidlack","year":"2000","journal-title":"Clin. Diagn. Lab. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1111\/j.1476-5381.2012.01952.x","article-title":"The endogenous opioid system in cocaine addiction: What lessons have opioid peptide and receptor knockout mice taught us?","volume":"166","author":"Yoo","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S0028-3908(02)00030-8","article-title":"Morphine induces apoptosis of human microglia and neurons","volume":"42","author":"Hu","year":"2002","journal-title":"Neuropharmacology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.neuron.2016.03.030","article-title":"Microglial TNF-\u03b1 Suppresses Cocaine-Induced Plasticity and Behavioral Sensitization","volume":"90","author":"Lewitus","year":"2016","journal-title":"Neuron"},{"key":"ref_45","first-page":"1","article-title":"Activin A is increased in the nucleus accumbens following a cocaine binge","volume":"7","author":"Wang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1093\/brain\/awu408","article-title":"New candidates for CD4 T cell pathogenicity in experimental neuroinflammation and multiple sclerosis","volume":"138","author":"Hoppmann","year":"2015","journal-title":"Brain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"23672","DOI":"10.3390\/ijms151223672","article-title":"P2X and P2Y receptors\u2014Role in the pathophysiology of the nervous system","volume":"15","author":"Tarnowski","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.brainresbull.2019.03.010","article-title":"Pharmacology of P2Y receptors","volume":"151","year":"2019","journal-title":"Brain Res. Bull."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1037\/a0016498","article-title":"Yoked Delivery of Cocaine Is Aversive and Protects Against the Motivation for Drug in Rats","volume":"123","author":"Twining","year":"2009","journal-title":"Behav. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"454","DOI":"10.3389\/fimmu.2018.00454","article-title":"CD86 expression by monocytes influence an immunomodulatory profile in asymptomatic patients with chronic chagas disease","volume":"9","author":"Pinto","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ejphar.2009.10.049","article-title":"Effects of imipramine or GABAB receptor ligands on the immobility, swimming and climbing in the forced swim test in rats following discontinuation of cocaine self-administration","volume":"627","author":"Frankowska","year":"2010","journal-title":"Eur. J. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/YPG.0b013e32835d7048","article-title":"Genetic association between RGS1 and internalizing disorders","volume":"23","author":"Hettema","year":"2013","journal-title":"Psychiatr. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41398-019-0486-6","article-title":"Dysregulation of a specific immune-related network of genes biologically defines a subset of schizophrenia","volume":"9","author":"Trossbach","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"9192","DOI":"10.1096\/fj.202000163R","article-title":"Maternal high-sugar diet changes offspring vulnerability to reinstatement of cocaine-seeking behavior: Role of melanocortin-4 receptors","volume":"34","author":"Frankowska","year":"2020","journal-title":"Faseb J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.pharep.2019.05.001","article-title":"Extinction training following cocaine or MDMA self-administration produces discrete changes in D2-like and mGlu5 receptor density in the rat brain","volume":"71","author":"Frankowska","year":"2019","journal-title":"Pharm. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1002\/hipo.22733","article-title":"Increased 5-hydroxymethylation levels in the hippocampus of rat extinguished from cocaine self-administration","volume":"27","author":"Frankowska","year":"2017","journal-title":"Hippocampus"},{"key":"ref_57","unstructured":"Paxinos, G., and Watson, C. (1998). The Rat Brain in Stereotaxic Coordinates, Academic Press. [4th ed.]."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/7970\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:29:03Z","timestamp":1760178543000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/7970"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,27]]},"references-count":57,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21217970"],"URL":"https:\/\/doi.org\/10.3390\/ijms21217970","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,27]]}}}