{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T03:25:56Z","timestamp":1794108356518,"version":"4.8.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T00:00:00Z","timestamp":1637884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Cocaine addiction is an acquired behavioral state developed in vulnerable individuals after cocaine exposure. It is characterized by compulsive drug-seeking and high vulnerability to relapse even after prolonged abstinence, associated with decreased neurogenesis in the hippocampus. This addictive state is hypothesized to be a form of \u201cmemory disease\u201d in which the drug exploits the physiological neuroplasticity mechanisms that mediate regular learning and memory processes. Therefore, a major focus of the field has been to identify the cocaine-induced neuroadaptations occurring in the usurped brain\u2019s reward circuit. The neurosteroid dehydroepiandrosterone (DHEA) affects brain cell morphology, differentiation, neurotransmission, and memory. It also reduces drug-seeking behavior in an animal model of cocaine self-administration. Here, we examined the long-lasting effects of DHEA treatment on the attenuation of cocaine-seeking behavior. We also examined its short- and long-term influence on hippocampal cells architecture (neurons and astrocytes). Using a behavioral examination, immunohistochemical staining, and diffusion tensor imaging, we found an immediate effect on tissue density and activation of astrocytes, which has a continuous beneficial effect on neurogenesis and tissue organization. This research emphasizes the requites concert between astrocytes and neurons in the rehabilitation from addiction behavior. Thus, DHEA may serve as a treatment that corrects brain damage following exposure to and abstinence from cocaine.<\/jats:p>","DOI":"10.3389\/fnins.2021.773197","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T07:39:00Z","timestamp":1638344340000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["The Effect of Dehydroepiandrosterone Treatment on Neurogenesis, Astrogliosis and Long-Term Cocaine-Seeking Behavior in a Cocaine Self-Administration Model in Rats"],"prefix":"10.3389","volume":"15","author":[{"given":"Hadas","family":"Ahdoot-Levi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ofri","family":"Croitoru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzofnat","family":"Bareli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einav","family":"Sudai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilla","family":"Pe\u00e9r-Nissan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avi","family":"Jacob","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Gispan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Maayan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abraham","family":"Weizman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gal","family":"Yadid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1016\/j.nurt.2007.05.011","article-title":"Diffusion tensor imaging of the brain.","volume":"4","author":"Alexander","year":"2007","journal-title":"Neurotherapeutics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.pneurobio.2016.03.010","article-title":"Astrocytes as a target for neuroprotection: modulation by progesterone and dehydroepiandrosterone.","volume":"144","author":"Arbo","year":"2016","journal-title":"Prog. Neurobiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1002\/hipo.20095","article-title":"A computational principle for hippocampal learning and neurogenesis.","volume":"15","author":"Becker","year":"2005","journal-title":"Hippocampus"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1046\/j.1460-9568.2003.02537.x","article-title":"Forebrain astroglial plasticity is induced following withdrawal from repeated cocaine administration.","volume":"17","author":"Bowers","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1134\/S199074781704002X","article-title":"The effect of dehydroepiandrosterone on inflammatory response of astroglial cells.","volume":"11","author":"Buyanova","year":"2017","journal-title":"Biochem. Suppl. Ser. A Membr. Cell Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/s0306-4530(01)00037-3","article-title":"Perturbations of plasma cortisol and DHEA-S following discontinuation of cocaine use in cocaine addicts.","volume":"27","author":"Buydens-Branchey","year":"2002","journal-title":"Psychoneuroendocrinology"},{"key":"B7","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.pop.2010.11.004","article-title":"Stimulant abuse: pharmacology, cocaine, methamphetamine, treatment, attempts at pharmacotherapy.","volume":"38","author":"Ciccarone","year":"2011","journal-title":"Prim. Care"},{"key":"B8","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1177\/1073858418809941","article-title":"Astrocytes: heterogeneous and dynamic phenotypes in neurodegeneration and innate immunity.","volume":"25","author":"Cunningham","year":"2019","journal-title":"Neuroscientist"},{"key":"B9","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1111\/j.1460-9568.2006.04924.x","article-title":"Chronic cocaine exposure impairs progenitor proliferation but spares survival and maturation of neural precursors in adult rat dentate gyrus.","volume":"24","author":"Dom\u00ednguez-Escrib\u00e0","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"B10","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1038\/sj.npp.1301013","article-title":"DHEA, a neurosteroid, decreases cocaine self-administration and reinstatement of cocaine-seeking behavior in rats.","volume":"31","author":"Doron","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1016\/j.biopsych.2014.02.005","article-title":"A shift in the role of glutamatergic signaling in the nucleus accumbens core with the development of an addicted phenotype.","volume":"76","author":"Doyle","year":"2014","journal-title":"Biol. Psychiatry"},{"key":"B12","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1002\/hipo.20161","article-title":"Opiates, psychostimulants, and adult hippocampal neurogenesis: insights for addiction and stem cell biology.","volume":"16","author":"Eisch","year":"2006","journal-title":"Hippocampus"},{"key":"B13","doi-asserted-by":"publisher","first-page":"7579","DOI":"10.1073\/pnas.120552597","article-title":"Opiates inhibit neurogenesis in the adult rat hippocampus.","volume":"97","author":"Eisch","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0165-0173(01)00088-1","article-title":"The neuropsychological basis of addictive behaviour.","volume":"36","author":"Everitt","year":"2001","journal-title":"Brain Res. Rev."},{"key":"B15","doi-asserted-by":"publisher","first-page":"2042","DOI":"10.1093\/cercor\/bhz221","article-title":"The relationship between axon density, myelination, and fractional anisotropy in the human corpus callosum.","volume":"30","author":"Friedrich","year":"2020","journal-title":"Cereb. Cortex"},{"key":"B16","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.tins.2018.08.005","article-title":"Drug-induced glucocorticoids and memory for substance use.","volume":"41","author":"Goldfarb","year":"2018","journal-title":"Trends Neurosci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.1002\/mrm.22155","article-title":"Assessment of the effects of cellular tissue properties on ADC measurements by numerical simulation of water diffusion.","volume":"62","author":"Harkins","year":"2009","journal-title":"Magn. Reson. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1016\/j.nlm.2008.06.008","article-title":"The hippocampal dentate gyrus is essential for generating contextual memories of fear and drug-induced reward.","volume":"90","author":"Hern\u00e1ndez-Rabaza","year":"2008","journal-title":"Neurobiol. Learn. Mem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"7919","DOI":"10.1073\/pnas.1230907100","article-title":"Selective impairment of hippocampal neurogenesis by chronic alcoholism: protective effects of an antioxidant.","volume":"100","author":"Herrera","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B20","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1046\/j.1460-9568.2002.02099.x","article-title":"Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression.","volume":"16","author":"Karishma","year":"2002","journal-title":"Eur. J. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1038\/scientificamerican0489-66","article-title":"Astrocytes.","volume":"260","author":"Kimelberg","year":"1989","journal-title":"Sci. Am."},{"key":"B22","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.euroneuro.2005.10.002","article-title":"Dehydroepiandrosterone (DHEA) attenuates cocaine-seeking behavior in the self-administration model in rats.","volume":"16","author":"Maayan","year":"2006","journal-title":"Eur. Neuropsychopharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1037\/0735-7044.120.2.401","article-title":"Dorsal hippocampus inhibition disrupts acquisition and expression, but not consolidation, of cocaine conditioned place preference.","volume":"120","author":"Meyers","year":"2006","journal-title":"Behav. Neurosci."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060863","article-title":"Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice.","volume":"8","author":"Moriguchi","year":"2013","journal-title":"PLoS One"},{"key":"B25","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.bbadis.2017.11.004","article-title":"Epigenetic regulation of astrocyte function in neuroinflammation and neurodegeneration.","volume":"1864","author":"Neal","year":"2018","journal-title":"Biochim. Biophys. Acta"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1002\/hbm.21511","article-title":"A rat brain MRI template with digital stereotaxic atlas of fine anatomical delineations in paxinos space and its automated application in voxel-wise analysis.","volume":"34","author":"Nie","year":"2013","journal-title":"Hum. Brain Mapp."},{"key":"B27","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1523\/JNEUROSCI.4256-09.2010","article-title":"Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction.","volume":"30","author":"Noonan","year":"2010","journal-title":"J. Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1111\/adb.12241","article-title":"Effect of dehydroepiandrosterone add-on therapy on mood, decision making and subsequent relapse of polydrug users.","volume":"21","author":"Ohana","year":"2016","journal-title":"Addict. Biol."},{"key":"B29","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2174\/1874473711003010049","article-title":"Review of treatment for cocaine dependence.","volume":"3","author":"Penberthy","year":"2010","journal-title":"Curr. Drug Abuse Rev."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/506191","article-title":"Dehydroepiandrosterone stimulates nerve growth factor and brain derived neurotrophic factor in cortical neurons.","volume":"2013","author":"Rahmani","year":"2013","journal-title":"Adv. Pharmacol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1002\/glia.20445","article-title":"S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage.","volume":"55","author":"Raponi","year":"2007","journal-title":"Glia"},{"key":"B32","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1001\/archpsyc.1991.01810250045005","article-title":"Psychiatric diagnoses of treatment-seeking cocaine abusers.","volume":"48","author":"Rounsaville","year":"1991","journal-title":"Arch. Gen. Psychiatry"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1126\/science.1178534","article-title":"The B73 maize genome: complexity, diversity, and dynamics.","volume":"326","author":"Schnable","year":"2009","journal-title":"Science"},{"key":"B34","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1177\/1073858413520347","article-title":"Astrocytic dysfunction and addiction: consequences of impaired glutamate homeostasis.","volume":"20","author":"Scofield","year":"2014","journal-title":"Neuroscientist"},{"key":"B35","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.biopsych.2015.12.022","article-title":"Cocaine self-administration and extinction leads to reduced glial fibrillary acidic protein expression and morphometric features of astrocytes in the nucleus accumbens core.","volume":"80","author":"Scofield","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"B36","doi-asserted-by":"publisher","first-page":"11041","DOI":"10.1523\/JNEUROSCI.2898-06.2006","article-title":"Amphetamine-induced place preference and conditioned motor sensitization requires activation of tyrosine kinase receptors in the hippocampus.","volume":"26","author":"Shen","year":"2006","journal-title":"J. Neurosci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1037\/1064-1297.12.2.126","article-title":"Participants receiving dehydroepiandrosterone during treatment for cocaine dependence show high rates of cocaine use in a placebo-controlled pilot study.","volume":"12","author":"Shoptaw","year":"2004","journal-title":"Exp. Clin. Psychopharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1111\/j.1369-1600.2010.00241.x","article-title":"High cocaine dosage decreases neurogenesis in the hippocampus and impairs working memory.","volume":"16","author":"Sudai","year":"2011","journal-title":"Addict. Biol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/s007020050012","article-title":"Adult treatment with methamphetamine transiently decreases dentate granule cell proliferation in the gerbil hippocampus.","volume":"107","author":"Teuchert-Noodt","year":"2000","journal-title":"J. Neural Transm."},{"key":"B40","first-page":"817","article-title":"Addiction and the brain: the role of neurotransmitters in the cause and treatment of drug dependence.","volume":"164","author":"Tomkins","year":"2001","journal-title":"CMAJ"},{"key":"B41","doi-asserted-by":"publisher","first-page":"68","DOI":"10.5607\/en.2013.22.2.68","article-title":"Role of glial cells in axonal regeneration.","volume":"22","author":"Toy","year":"2013","journal-title":"Exp. Neurobiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/j.pneurobio.2015.09.003","article-title":"Translational potential of astrocytes in brain disorders.","volume":"144","author":"Verkhratsky","year":"2016","journal-title":"Prog. Neurobiol."},{"key":"B43","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.neubiorev.2010.03.003","article-title":"The role of dehydroepiandrosterone (DHEA) in drug-seeking behavior.","volume":"35","author":"Yadid Gal","year":"2010","journal-title":"Neurosci. Biobehav. Rev."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.773197\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T07:39:09Z","timestamp":1638344349000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2021.773197\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,26]]},"references-count":43,"alternative-id":["10.3389\/fnins.2021.773197"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2021.773197","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,26]]},"article-number":"773197"}}