{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T22:52:13Z","timestamp":1791845533227,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T00:00:00Z","timestamp":1657584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006109","name":"VEGA","doi-asserted-by":"publisher","award":["2\/0037\/19"],"award-info":[{"award-number":["2\/0037\/19"]}],"id":[{"id":"10.13039\/501100006109","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006109","name":"VEGA","doi-asserted-by":"publisher","award":["2\/0010\/22"],"award-info":[{"award-number":["2\/0010\/22"]}],"id":[{"id":"10.13039\/501100006109","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Aberrant neurogenesis in the subventricular zone (SVZ) and hippocampus (HIP) contributes to schizophrenia pathogenesis. Haloperidol (HAL) and olanzapine (OLA), commonly prescribed antipsychotics for schizophrenia treatment, affect neurogenesis too. The effect of HAL and OLA on an mHippoE-2 cell line was studied in vitro where we measured the cell number and projection length. In vivo, we studied the gene expression of DCX, Sox2, BDNF, and NeuN in the SVZ and HIP in an MK-801-induced animal schizophrenia model. Cells were incubated with HAL, OLA, and MK-801 for 24, 48, and 72 h. Animals were injected for 6 days with saline or MK801 (0.5 mg\/kg), and from the 7th day with either vehicle HAL (1 mg\/kg) or OLA (2 mg\/kg), for the next 7 days. In vitro, HAL and OLA dose\/time-dependently suppressed cells\u2019 proliferation and shortened their projection length. HAL\/OLA co-treatment with MK-801 for 24 h reversed HAL\u2019s\/OLA\u2019s inhibitory effect. In vivo, HAL and OLA suppressed DCX and NeuN genes\u2019 expression in the HIP and SVZ. MK-801 decreased DCX and NeuN genes\u2019 expression in the HIP and OLA prevented this effect. The data suggest that subchronic HAL\/OLA treatment can inhibit DCX and NeuN expression. In an MK-801 schizophrenia model, OLA reversed the MK-801 inhibitory effect on DCX and NeuN and HAL reversed the effect on DCX expression; however, only in the HIP.<\/jats:p>","DOI":"10.3390\/ijms23147711","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T20:52:41Z","timestamp":1657659161000},"page":"7711","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Effect of Haloperidol and Olanzapine on Hippocampal Cells\u2019 Proliferation in Animal Model of Schizophrenia"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2144-0534","authenticated-orcid":false,"given":"Jana","family":"Osacka","sequence":"first","affiliation":[{"name":"Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kiss","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Bacova","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4643-7040","authenticated-orcid":false,"given":"Andrej","family":"Tillinger","sequence":"additional","affiliation":[{"name":"Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, D\u00fabravsk\u00e1 Cesta 9, 845 05 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/YCO.0000000000000501","article-title":"Important unanswered questions about adult neurogenesis in schizophrenia","volume":"32","author":"Weissleder","year":"2019","journal-title":"Curr. Opin. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/npp.2014.230","article-title":"Adult neurogenesis and mental illness","volume":"40","author":"Schoenfeld","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1038\/nrn.2017.125","article-title":"Genetic insights into the neurodevelopmental origins of schizophrenia","volume":"18","author":"Birnbaum","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.brainres.2017.09.006","article-title":"Chronic atypical antipsychotics, but not haloperidol, increase neurogenesis in the hippocampus of adult mouse","volume":"1676","author":"Chikama","year":"2017","journal-title":"Brain Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s10571-014-0058-5","article-title":"Hypothalamic subependymal niche: A novel site of the adult neurogenesis","volume":"34","author":"Wiaderkiewicz","year":"2014","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.yfrne.2014.11.004","article-title":"Seasonal regulation of structural plasticity and neurogenesis in the adult mammalian brain: Focus on the sheep hypothalamus","volume":"37","author":"Migaud","year":"2015","journal-title":"Front. Neuroendocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1007\/s00429-015-0995-x","article-title":"Voluntary exercise induces neurogenesis in the hypothalamus and ependymal lining of the third ventricle","volume":"221","author":"Niwa","year":"2016","journal-title":"Brain Struct. Funct."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.neuroscience.2018.12.037","article-title":"High-fat Diet and Physical Exercise Differentially Modulate Adult Neurogenesis in the Mouse Hypothalamus","volume":"400","author":"Klein","year":"2019","journal-title":"Neuroscience"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Grinchii, D., and Dremencov, E. (2020). Mechanism of Action of Atypical Antipsychotic Drugs in Mood Disorders. Int. J. Mol. Sci., 21.","DOI":"10.20944\/preprints202011.0143.v1"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.pnpbp.2011.08.010","article-title":"Neurotoxic\/neuroprotective activity of haloperidol, risperidone and paliperidone in neuroblastoma cells","volume":"36","author":"Gasso","year":"2012","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1111\/pcn.12242","article-title":"Psychopharmacology of atypical antipsychotic drugs: From the receptor binding profile to neuroprotection and neurogenesis","volume":"69","author":"Kusumi","year":"2015","journal-title":"Psychiatry Clin. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.schres.2019.04.009","article-title":"Neuroprotective effects of the second generation antipsychotics","volume":"208","author":"Chen","year":"2019","journal-title":"Schizophr. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s00702-004-0109-z","article-title":"Neurotoxic potential of haloperidol in comparison with risperidone: Implication of Akt-mediated signal changes by haloperidol","volume":"111","author":"Ukai","year":"2004","journal-title":"J. Neural Transm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.neuint.2006.09.015","article-title":"Haloperidol induces neurotoxicity by the NMDA receptor downstream signaling pathway, alternative from glutamate excitotoxicity","volume":"50","author":"Zhuravliova","year":"2007","journal-title":"Neurochem. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1017\/S1461145712001277","article-title":"Efficacy and safety of individual second-generation vs. first-generation antipsychotics in first-episode psychosis: A systematic review and meta-analysis","volume":"16","author":"Zhang","year":"2013","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1002\/jnr.10281","article-title":"Atypical neuroleptics stimulate neurogenesis in adult rat brain","volume":"69","author":"Wakade","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s00213-011-2291-7","article-title":"Neuroprotection of paliperidone on SH-SY5Y cells against beta-amyloid peptide(25\u201335), N-methyl-4-phenylpyridinium ion, and hydrogen peroxide-induced cell death","volume":"217","author":"Yang","year":"2011","journal-title":"Psychopharmacology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00441-011-1196-4","article-title":"Immunohistological markers for proliferative events, gliogenesis, and neurogenesis within the adult hippocampus","volume":"345","year":"2011","journal-title":"Cell Tissue Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ejphar.2010.10.064","article-title":"Aripiprazole protects cortical neurons from glutamate toxicity","volume":"651","author":"Koprivica","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1007\/s12035-015-9217-z","article-title":"Paliperidone Protects SH-SY5Y Cells against MK-801-Induced Neuronal Damage through Inhibition of Ca2+ Influx and Regulation of SIRT1\/miR-134 Signal Pathway","volume":"53","author":"Zhu","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1756-6606-6-24","article-title":"Acute 5-HT7 receptor activation increases NMDA-evoked currents and differentially alters NMDA receptor subunit phosphorylation and trafficking in hippocampal neurons","volume":"6","author":"Vasefi","year":"2013","journal-title":"Mol. Brain"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"136098","DOI":"10.1016\/j.neulet.2021.136098","article-title":"Minireview: Animal model of schizophrenia from the perspective of behavioral pharmacology: Effect of treatment on cognitive functions","volume":"761","author":"Vales","year":"2021","journal-title":"Neurosci. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"219","DOI":"10.4252\/wjsc.v14.i3.219","article-title":"Adult neural stem cells and schizophrenia","volume":"14","author":"Hu","year":"2022","journal-title":"World J. Stem Cells"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.schres.2006.09.030","article-title":"Adult neurogenesis and schizophrenia: A window on abnormal early brain development?","volume":"90","author":"Toro","year":"2007","journal-title":"Schizophr. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s10571-010-9619-4","article-title":"Effects of treadmill exercise combined with MK 801 treatment on neuroblast differentiation in the dentate gyrus in rats","volume":"31","author":"Choi","year":"2011","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"172830","DOI":"10.1016\/j.pbb.2019.172830","article-title":"Intracellular mechanisms and behavioral changes in mouse model of attention deficit hyperactivity disorder: Importance of age-specific NMDA receptor blockade","volume":"188","author":"Kawade","year":"2020","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"109024","DOI":"10.1016\/j.neuropharm.2022.109024","article-title":"Differential expression of miR-148b, miR-129-2 and miR-296 in animal models of schizophrenia-Relevance to NMDA receptor hypofunction","volume":"210","author":"Gunasekaran","year":"2022","journal-title":"Neuropharmacology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"ENEURO.0566-20.2021","DOI":"10.1523\/ENEURO.0566-20.2021","article-title":"Role of NMDA Receptors in Adult Neurogenesis and Normal Development of the Dentate Gyrus","volume":"8","author":"Amellem","year":"2021","journal-title":"eNeuro"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/sj.npp.1300422","article-title":"Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus","volume":"29","author":"Halim","year":"2004","journal-title":"Neuropsychopharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.biopsych.2004.07.008","article-title":"Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat","volume":"56","author":"Kodama","year":"2004","journal-title":"Biol. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"458","DOI":"10.2174\/1871527317666180627113544","article-title":"Long-term Treatment with Olanzapine Increases the Number of Sox2 and Doublecortin Expressing Cells in the Adult Subventricular Zone","volume":"17","author":"Lasut","year":"2018","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/j.pharep.2015.04.014","article-title":"Effects of neuroleptics administration on adult neurogenesis in the rat hypothalamus","volume":"67","author":"Rojczyk","year":"2015","journal-title":"Pharmacol. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.pnpbp.2013.12.011","article-title":"The effect of dopamine on adult hippocampal neurogenesis","volume":"50","author":"Takamura","year":"2014","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_34","first-page":"14","article-title":"Oppositional effects of serotonin receptors 5-HT1a, 2, and 2c in the regulation of adult hippocampal neurogenesis","volume":"3","author":"Klempin","year":"2010","journal-title":"Front. Mol. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2682037","DOI":"10.1155\/2018\/2682037","article-title":"Effects of Antipsychotic Drugs on the Epigenetic Modification of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampi of Chronic Restraint Stress Rats","volume":"2018","author":"Seo","year":"2018","journal-title":"Neural Plast."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"153","DOI":"10.2478\/enr-2021-0016","article-title":"Haloperidol and aripiprazole impact on the BDNF and glucocorticoid receptor levels in the rat hippocampus and prefrontal cortex: Effect of the chronic mild stress","volume":"55","author":"Osacka","year":"2021","journal-title":"Endocr. Regul."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"114643","DOI":"10.1016\/j.taap.2019.114643","article-title":"Modeling of antipsychotic-induced metabolic alterations in mice: An experimental approach precluding psychosis as a predisposing factor","volume":"378","author":"Singh","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"279","DOI":"10.9758\/cpn.2016.14.3.279","article-title":"Differential Effects of Olanzapine and Haloperidol on MK-801-induced Memory Impairment in Mice","volume":"14","author":"Song","year":"2016","journal-title":"Clin. Psychopharmacol. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1254\/jphs.FP0061424","article-title":"Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine","volume":"103","author":"Maeda","year":"2007","journal-title":"J. Pharmacol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1002\/stem.3457","article-title":"Dopamine regulates adult neurogenesis in the ventricular-subventricular zone via dopamine D3 angiotensin type 2 receptor interactions","volume":"39","author":"Parga","year":"2021","journal-title":"Stem Cells"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nn.2592","article-title":"Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors","volume":"13","author":"Higley","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Frau, R., Pardu, A., Godar, S., Bini, V., and Bortolato, M. (2022). Combined Antagonism of 5-HT2 and NMDA Receptors Reduces the Aggression of Monoamine Oxidase a Knockout Mice. Pharmaceuticals, 15.","DOI":"10.3390\/ph15020213"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1038\/sj.npp.1300993","article-title":"Glial-neuronal interactions are impaired in the schizophrenia model of repeated MK801 exposure","volume":"31","author":"Kondziella","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"ref_44","unstructured":"Paxinos, G., and Watson, C. (1997). The Rat Brain in Stereotaxic Coordinates, Academic Press, Inc.. [3rd ed.]."},{"key":"ref_45","unstructured":"Palkovits, M., and Brownstein, M.J. (1988). Maps and Guide to Microdissection of the Rat Brain, Elsevier."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7711\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:49:05Z","timestamp":1760140145000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/14\/7711"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,12]]},"references-count":46,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23147711"],"URL":"https:\/\/doi.org\/10.3390\/ijms23147711","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,12]]}}}