{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:47:04Z","timestamp":1790869624819,"version":"4.1.0"},"reference-count":77,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,8,30]],"date-time":"2018-08-30T00:00:00Z","timestamp":1535587200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,8,30]],"date-time":"2018-08-30T00:00:00Z","timestamp":1535587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Autistic spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairment in social communication and restricted\/repetitive behavior patterns or interests. Antagonists targeting histamine H3 receptor (H3R) are considered potential therapeutic agents for the therapeutic management of different brain disorders, e.g., cognitive impairments. Therefore, the effects of subchronic treatment with the potent and selective H3R antagonist DL77 (5, 10, or 15\u2009mg\/kg, i.p.) on sociability, social novelty, anxiety, and aggressive\/repetitive behavior in male Tuck-Ordinary (TO) mice with ASD-like behaviors induced by prenatal exposure to valproic acid (VPA, 500\u2009mg\/kg, i.p.) were evaluated using the three-chamber test (TCT), marble burying test (MBT), nestlet shredding test (NST), and elevated plus maze (EPM) test. The results showed that VPA-exposed mice exhibited significantly lower sociability and social novelty preference compared to VPA-exposed mice that were pretreated with DL77 (10 or 15\u2009mg\/kg, i.p.). VPA-exposed mice presented a significantly higher percentage of buried marbles in MBT and shredded nestlet significantly more in NST compared to the control groups. However, VPA-exposed animals pretreated with DL77 (10 or 15\u2009mg\/kg, i.p.) buried a reduced percentage of marbles in MBT and presented a significantly lower percentage of shredding behavior in NST. On the other hand, pretreatment with DL77 (5, 10, or 15\u2009mg\/kg, i.p.) failed to restore the disturbed anxiety levels and hyperactivity observed in VPA-exposed animals in EPM, whereas the reference drug donepezil (DOZ, 1\u2009mg\/kg, i.p.) significantly palliated the anxiety and reduced the hyperactivity measures of VPA-exposed mice. Furthermore, pretreatment with DL77 (10 or 15\u2009mg\/kg, i.p.) modulated oxidative stress status by increasing GSH and decreasing MDA, and it attenuated the proinflammatory cytokines IL-1\u03b2, IL-6 and TNF-\u03b1 exacerbated by lipopolysaccharide (LPS) challenge, in VPA-exposed mouse brain tissue. Taken together, these results provide evidence that modulation of brain histaminergic neurotransmission, such as by subchronic administration of the H3R antagonist DL77, may serve as an effective pharmacological therapeutic target to rescue ASD-like behaviors in VPA-exposed animals, although further investigations are necessary to corroborate and expand these initial data.<\/jats:p>","DOI":"10.1038\/s41598-018-31385-7","type":"journal-article","created":{"date-parts":[[2018,8,24]],"date-time":"2018-08-24T09:49:53Z","timestamp":1535104193000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism"],"prefix":"10.1038","volume":"8","author":[{"given":"Nermin","family":"Eissa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petrilla","family":"Jayaprakash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheikh","family":"Azimullah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreesh K.","family":"Ojha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Al-Houqani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fakhreya Y.","family":"Jalal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"\u0141a\u017cewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Kie\u0107-Kononowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassem","family":"Sadek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,8,30]]},"reference":[{"key":"31385_CR1","doi-asserted-by":"publisher","unstructured":"Baronio, D. et al. Effects of an H3R antagonist on the animal model of autism induced by prenatal exposure to valproic acid. Plos One 10, e0116363, https:\/\/doi.org\/10.1371\/journal.pone.0116363 (2015).","DOI":"10.1371\/journal.pone.0116363"},{"key":"31385_CR2","doi-asserted-by":"crossref","unstructured":"Andres, C. Molecular genetics and animal models in autistic disorder. Brain Res Bull 57, 109\u2013119, doi:S0361923001006426 (2002).","DOI":"10.1016\/S0361-9230(01)00642-6"},{"key":"31385_CR3","unstructured":"WHO | Autism spectrum disorders. WHO, doi:\/entity\/mediacentre\/factsheets\/autism-spectrum-disorders\/en\/index.html (2016)."},{"key":"31385_CR4","unstructured":"Srinivasan, P. A review of dietary interventions in autism. Ann Clin Psychiatry 21, 237\u2013247, doi:acp_2104d (2009)."},{"key":"31385_CR5","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1007\/s10803-006-0192-0","volume":"37","author":"E Hanson","year":"2007","unstructured":"Hanson, E. et al. Use of complementary and alternative medicine among children diagnosed with autism spectrum disorder. J Autism Dev Disord 37, 628\u2013636, https:\/\/doi.org\/10.1007\/s10803-006-0192-0 (2007).","journal-title":"J Autism Dev Disord"},{"key":"31385_CR6","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1016\/S0301-0082(00)00039-3","volume":"63","author":"RE Brown","year":"2001","unstructured":"Brown, R. E., Stevens, D. R. & Haas, H. L. The physiology of brain histamine. Prog Neurobiol 63, 637\u2013672 (2001).","journal-title":"Prog Neurobiol"},{"key":"31385_CR7","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.neuropharm.2015.11.005","volume":"106","author":"B Sadek","year":"2016","unstructured":"Sadek, B. & Stark, H. Cherry-picked ligands at histamine receptor subtypes. Neuropharmacology 106, 56\u201373, https:\/\/doi.org\/10.1016\/j.neuropharm.2015.11.005 (2016).","journal-title":"Neuropharmacology"},{"key":"31385_CR8","doi-asserted-by":"crossref","unstructured":"Sander, K., Kottke, T. & Stark, H. Histamine H3 receptor antagonists go to clinics. Biol Pharm Bull 31, 2163\u20132181, doi:JST.JSTAGE\/bpb\/31.2163 (2008).","DOI":"10.1248\/bpb.31.2163"},{"key":"31385_CR9","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.bbr.2016.06.051","volume":"312","author":"B Sadek","year":"2016","unstructured":"Sadek, B., Saad, A., Sadeq, A., Jalal, F. & Stark, H. Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases. Behav Brain Res 312, 415\u2013430, https:\/\/doi.org\/10.1016\/j.bbr.2016.06.051 (2016).","journal-title":"Behav Brain Res"},{"key":"31385_CR10","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1124\/pr.114.010249","volume":"67","author":"P Panula","year":"2015","unstructured":"Panula, P. et al. International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors. Pharmacological reviews 67, 601\u2013655, https:\/\/doi.org\/10.1124\/pr.114.010249 (2015).","journal-title":"Pharmacological reviews"},{"key":"31385_CR11","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1007\/s10803-006-0131-0","volume":"36","author":"HH Wong","year":"2006","unstructured":"Wong, H. H. & Smith, R. G. Patterns of complementary and alternative medical therapy use in children diagnosed with autism spectrum disorders. J Autism Dev Disord 36, 901\u2013909, https:\/\/doi.org\/10.1007\/s10803-006-0131-0 (2006).","journal-title":"J Autism Dev Disord"},{"key":"31385_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pharmthera.2004.05.001","volume":"103","author":"JM Witkin","year":"2004","unstructured":"Witkin, J. M. & Nelson, D. L. Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system. Pharmacol Ther 103, 1\u201320, https:\/\/doi.org\/10.1016\/j.pharmthera.2004.05.001 (2004).","journal-title":"Pharmacol Ther"},{"issue":"Suppl 10","key":"31385_CR13","first-page":"26","volume":"66","author":"RL Findling","year":"2005","unstructured":"Findling, R. L. Pharmacologic treatment of behavioral symptoms in autism and pervasive developmental disorders. J Clin Psychiatry 66(Suppl 10), 26\u201331 (2005).","journal-title":"J Clin Psychiatry"},{"key":"31385_CR14","doi-asserted-by":"publisher","first-page":"597","DOI":"10.2165\/11591700-000000000-00000","volume":"25","author":"JL Matson","year":"2011","unstructured":"Matson, J. L., Sipes, M., Fodstad, J. C. & Fitzgerald, M. E. Issues in the management of challenging behaviours of adults with autism spectrum disorder. CNS Drugs 25, 597\u2013606, https:\/\/doi.org\/10.2165\/11591700-000000000-00000 (2011).","journal-title":"CNS Drugs"},{"key":"31385_CR15","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1152\/physrev.00043.2007","volume":"88","author":"HL Haas","year":"2008","unstructured":"Haas, H. L., Sergeeva, O. A. & Selbach, O. Histamine in the nervous system. Physiol Rev 88, 1183\u20131241, https:\/\/doi.org\/10.1152\/physrev.00043.2007 (2008).","journal-title":"Physiol Rev"},{"key":"31385_CR16","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.bbi.2016.07.002","volume":"57","author":"L Frick","year":"2016","unstructured":"Frick, L., Rapanelli, M., Abbasi, E., Ohtsu, H. & Pittenger, C. Histamine regulation of microglia: Gene-environment interaction in the regulation of central nervous system inflammation. Brain, Behavior, and Immunity 57, 326\u2013337, https:\/\/doi.org\/10.1016\/j.bbi.2016.07.002 (2016).","journal-title":"Brain, Behavior, and Immunity"},{"key":"31385_CR17","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1007\/s12035-014-8697-6","volume":"49","author":"H Dong","year":"2014","unstructured":"Dong, H. et al. Histamine induces upregulated expression of histamine receptors and increases release of inflammatory mediators from microglia. Molecular neurobiology 49, 1487\u20131500, https:\/\/doi.org\/10.1007\/s12035-014-8697-6 (2014).","journal-title":"Molecular neurobiology"},{"key":"31385_CR18","doi-asserted-by":"publisher","first-page":"120","DOI":"10.3389\/fncel.2014.00120","volume":"8","author":"SM Rocha","year":"2014","unstructured":"Rocha, S. M., Pires, J., Esteves, M., Graca, B. & Bernardino, L. Histamine: a new immunomodulatory player in the neuron-glia crosstalk. Frontiers in cellular neuroscience 8, 120, https:\/\/doi.org\/10.3389\/fncel.2014.00120 (2014).","journal-title":"Frontiers in cellular neuroscience"},{"key":"31385_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-9-90","volume":"9","author":"R Ferreira","year":"2012","unstructured":"Ferreira, R. et al. Histamine modulates microglia function. Journal of neuroinflammation 9, 90, https:\/\/doi.org\/10.1186\/1742-2094-9-90 (2012).","journal-title":"Journal of neuroinflammation"},{"key":"31385_CR20","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1111\/bph.14124","volume":"175","author":"D Baronio","year":"2018","unstructured":"Baronio, D. et al. Embryonic exposure to valproic acid affects the histaminergic system and the social behaviour of adult zebrafish (Danio rerio). Br J Pharmacol 175, 797\u2013809, https:\/\/doi.org\/10.1111\/bph.14124 (2018).","journal-title":"Br J Pharmacol"},{"key":"31385_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2017.87","volume":"7","author":"C Wright","year":"2017","unstructured":"Wright, C. et al. Altered expression of histamine signaling genes in autism spectrum disorder. Transl Psychiatry 7, e1126, https:\/\/doi.org\/10.1038\/tp.2017.87 (2017).","journal-title":"Transl Psychiatry"},{"key":"31385_CR22","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/0166-2236(91)90034-R","volume":"14","author":"H Wada","year":"1991","unstructured":"Wada, H., Inagaki, N., Yamatodani, A. & Watanabe, T. Is the histaminergic neuron system a regulatory center for whole-brain activity? Trends Neurosci 14, 415\u2013418 (1991).","journal-title":"Trends Neurosci"},{"key":"31385_CR23","doi-asserted-by":"publisher","first-page":"3522","DOI":"10.1016\/j.bmc.2006.01.013","volume":"14","author":"D Lazewska","year":"2006","unstructured":"Lazewska, D. et al. Ether derivatives of 3-piperidinopropan-1-ol as non-imidazole histamine H3 receptor antagonists. Bioorg Med Chem 14, 3522\u20133529, https:\/\/doi.org\/10.1016\/j.bmc.2006.01.013 (2006).","journal-title":"Bioorg Med Chem"},{"key":"31385_CR24","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.neuropharm.2015.10.023","volume":"106","author":"B Sadek","year":"2016","unstructured":"Sadek, B. et al. Anticonvulsant and procognitive properties of the non-imidazole histamine H3 receptor antagonist DL77 in male adult rats. Neuropharmacology 106, 46\u201355, https:\/\/doi.org\/10.1016\/j.neuropharm.2015.10.023 (2016).","journal-title":"Neuropharmacology"},{"key":"31385_CR25","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.physbeh.2015.07.012","volume":"151","author":"A Bahi","year":"2015","unstructured":"Bahi, A., Sadek, B., Nurulain, S. M., Lazewska, D. & Kiec-Kononowicz, K. The novel non-imidazole histamine H3 receptor antagonist DL77 reduces voluntary alcohol intake and ethanol-induced conditioned place preference in mice. Physiol Behav 151, 189\u2013197, https:\/\/doi.org\/10.1016\/j.physbeh.2015.07.012 (2015).","journal-title":"Physiol Behav"},{"key":"31385_CR26","doi-asserted-by":"publisher","first-page":"5982","DOI":"10.1016\/j.bmc.2008.04.058","volume":"16","author":"J Handzlik","year":"2008","unstructured":"Handzlik, J. et al. Synthesis, alpha 1-adrenoceptor antagonist activity, and SAR study of novel arylpiperazine derivatives of phenytoin. Bioorg Med Chem 16, 5982\u20135998, https:\/\/doi.org\/10.1016\/j.bmc.2008.04.058 (2008).","journal-title":"Bioorg Med Chem"},{"key":"31385_CR27","doi-asserted-by":"publisher","first-page":"42","DOI":"10.3389\/fnins.2018.00042","volume":"12","author":"N Eissa","year":"2018","unstructured":"Eissa, N. et al. The Histamine H3 Receptor Antagonist DL77 Ameliorates MK801-Induced Memory Deficits in Rats. Front Neurosci 12, 42, https:\/\/doi.org\/10.3389\/fnins.2018.00042 (2018).","journal-title":"Front Neurosci"},{"key":"31385_CR28","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/2053-8871-1-5","volume":"1","author":"B Li","year":"2014","unstructured":"Li, B., Zhu, J. N. & Wang, J. J. Histaminergic afferent system in the cerebellum: structure and function. Cerebellum Ataxias 1, 5, https:\/\/doi.org\/10.1186\/2053-8871-1-5 (2014).","journal-title":"Cerebellum Ataxias"},{"key":"31385_CR29","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1002\/aur.1338","volume":"7","author":"L Lucchina","year":"2014","unstructured":"Lucchina, L. & Depino, A. M. Altered peripheral and central inflammatory responses in a mouse model of autism. Autism Res 7, 273\u2013289, https:\/\/doi.org\/10.1002\/aur.1338 (2014).","journal-title":"Autism Res"},{"key":"31385_CR30","doi-asserted-by":"publisher","first-page":"179","DOI":"10.2147\/DDDT.S144730","volume":"12","author":"SM Bastaki","year":"2018","unstructured":"Bastaki, S. M. et al. Anticonvulsant and reproductive toxicological studies of the imidazole-based histamine H3R antagonist 2-18 in mice. Drug Des Devel Ther 12, 179\u2013194, https:\/\/doi.org\/10.2147\/DDDT.S144730 (2018).","journal-title":"Drug Des Devel Ther"},{"key":"31385_CR31","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1017\/S1461145711001714","volume":"16","author":"S Kataoka","year":"2013","unstructured":"Kataoka, S. et al. Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid. Int J Neuropsychopharmacol 16, 91\u2013103, https:\/\/doi.org\/10.1017\/s1461145711001714 (2013).","journal-title":"Int J Neuropsychopharmacol"},{"key":"31385_CR32","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.pbb.2014.08.013","volume":"126","author":"K Takuma","year":"2014","unstructured":"Takuma, K. et al. Chronic treatment with valproic acid or sodium butyrate attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism. Pharmacol Biochem Behav 126, 43\u201349, https:\/\/doi.org\/10.1016\/j.pbb.2014.08.013 (2014).","journal-title":"Pharmacol Biochem Behav"},{"key":"31385_CR33","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1038\/npp.2013.274","volume":"39","author":"G Karvat","year":"2014","unstructured":"Karvat, G. & Kimchi, T. Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism. Neuropsychopharmacology 39, 831\u2013840, https:\/\/doi.org\/10.1038\/npp.2013.274 (2014).","journal-title":"Neuropsychopharmacology"},{"key":"31385_CR34","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.neuropharm.2016.06.010","volume":"109","author":"G Provensi","year":"2016","unstructured":"Provensi, G., Costa, A., Passani, M. B. & Blandina, P. Donepezil, an acetylcholine esterase inhibitor, and ABT-239, a histamine H3 receptor antagonist\/inverse agonist, require the integrity of brain histamine system to exert biochemical and procognitive effects in the mouse. Neuropharmacology 109, 139\u2013147, https:\/\/doi.org\/10.1016\/j.neuropharm.2016.06.010 (2016).","journal-title":"Neuropharmacology"},{"key":"31385_CR35","doi-asserted-by":"publisher","first-page":"5499","DOI":"10.2147\/dddt.s90616","volume":"9","author":"S Ojha","year":"2015","unstructured":"Ojha, S., Javed, H., Azimullah, S., Abul Khair, S. B. & Haque, M. E. Neuroprotective potential of ferulic acid in the rotenone model of Parkinson\u2019s disease. Drug Des Devel Ther 9, 5499\u20135510, https:\/\/doi.org\/10.2147\/dddt.s90616 (2015).","journal-title":"Drug Des Devel Ther"},{"key":"31385_CR36","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1111\/j.1601-1848.2004.00076.x","volume":"3","author":"SS Moy","year":"2004","unstructured":"Moy, S. S. et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav 3, 287\u2013302, https:\/\/doi.org\/10.1111\/j.1601-1848.2004.00076.x (2004).","journal-title":"Genes Brain Behav"},{"key":"31385_CR37","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1038\/nrn2851","volume":"11","author":"JL Silverman","year":"2010","unstructured":"Silverman, J. L., Yang, M., Lord, C. & Crawley, J. N. Behavioural phenotyping assays for mouse models of autism. Nature reviews. Neuroscience 11, 490\u2013502, https:\/\/doi.org\/10.1038\/nrn2851 (2010).","journal-title":"Nature reviews. Neuroscience"},{"key":"31385_CR38","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.neulet.2014.09.039","volume":"583","author":"V Bambini-Junior","year":"2014","unstructured":"Bambini-Junior, V. et al. Resveratrol prevents social deficits in animal model of autism induced by valproic acid. Neurosci Lett 583, 176\u2013181, https:\/\/doi.org\/10.1016\/j.neulet.2014.09.039 (2014).","journal-title":"Neurosci Lett"},{"key":"31385_CR39","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1002\/mrdd.20039","volume":"10","author":"JN Crawley","year":"2004","unstructured":"Crawley, J. N. Designing mouse behavioral tasks relevant to autistic-like behaviors. Mental retardation and developmental disabilities research reviews 10, 248\u2013258, https:\/\/doi.org\/10.1002\/mrdd.20039 (2004).","journal-title":"Mental retardation and developmental disabilities research reviews"},{"key":"31385_CR40","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1111\/j.1601-183X.2004.00071.x","volume":"3","author":"JJ Nadler","year":"2004","unstructured":"Nadler, J. J. et al. Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav 3, 303\u2013314, https:\/\/doi.org\/10.1111\/j.1601-183X.2004.00071.x (2004).","journal-title":"Genes Brain Behav"},{"key":"31385_CR41","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1007\/s00213-009-1466-y","volume":"204","author":"A Thomas","year":"2009","unstructured":"Thomas, A. et al. Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology (Berl) 204, 361\u2013373, https:\/\/doi.org\/10.1007\/s00213-009-1466-y (2009).","journal-title":"Psychopharmacology (Berl)"},{"key":"31385_CR42","doi-asserted-by":"publisher","first-page":"627","DOI":"10.2147\/DDDT.S63088dddt-8-627","volume":"8","author":"A Bahi","year":"2014","unstructured":"Bahi, A., Schwed, J. S., Walter, M., Stark, H. & Sadek, B. Anxiolytic and antidepressant-like activities of the novel and potent non-imidazole histamine H(3) receptor antagonist ST-1283. Drug Des Devel Ther 8, 627\u2013637, https:\/\/doi.org\/10.2147\/DDDT.S63088dddt-8-627 (2014).","journal-title":"Drug Des Devel Ther"},{"key":"31385_CR43","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2016.77","volume":"6","author":"TC Theoharides","year":"2016","unstructured":"Theoharides, T. C., Tsilioni, I., Patel, A. B. & Doyle, R. Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders. Transl Psychiatry 6, e844, https:\/\/doi.org\/10.1038\/tp.2016.77 (2016).","journal-title":"Transl Psychiatry"},{"key":"31385_CR44","doi-asserted-by":"publisher","unstructured":"Angoa-Perez, M., Kane, M. J., Briggs, D. I., Francescutti, D. M. & Kuhn, D. M. Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice. Journal of visualized experiments: JoVE, 50978, https:\/\/doi.org\/10.3791\/50978 (2013).","DOI":"10.3791\/50978"},{"key":"31385_CR45","doi-asserted-by":"publisher","first-page":"e104927","DOI":"10.1371\/journal.pone.0104927","volume":"9","author":"JW Kim","year":"2014","unstructured":"Kim, J. W. et al. Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic acid-induced animal model of autism. Plos One 9, e104927, https:\/\/doi.org\/10.1371\/journal.pone.0104927 (2014).","journal-title":"Plos One"},{"key":"31385_CR46","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.pbb.2013.01.023","volume":"105","author":"A Bahi","year":"2013","unstructured":"Bahi, A. Individual differences in elevated plus-maze exploration predicted higher ethanol consumption and preference in outbred mice. Pharmacol Biochem Behav 105, 83\u201388, https:\/\/doi.org\/10.1016\/j.pbb.2013.01.023 (2013).","journal-title":"Pharmacol Biochem Behav"},{"key":"31385_CR47","doi-asserted-by":"publisher","first-page":"441","DOI":"10.3109\/10253890.2012.754419","volume":"16","author":"A Bahi","year":"2013","unstructured":"Bahi, A. Increased anxiety, voluntary alcohol consumption and ethanol-induced place preference in mice following chronic psychosocial stress. Stress (Amsterdam, Netherlands) 16, 441\u2013451, https:\/\/doi.org\/10.3109\/10253890.2012.754419 (2013).","journal-title":"Stress (Amsterdam, Netherlands)"},{"key":"31385_CR48","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/j.euroneuro.2012.01.008","volume":"22","author":"A Bahi","year":"2012","unstructured":"Bahi, A. & Dreyer, J. L. Hippocampus-specific deletion of tissue plasminogen activator \u201ctPA\u201d in adult mice impairs depression- and anxiety-like behaviors. Eur Neuropsychopharmacol 22, 672\u2013682, https:\/\/doi.org\/10.1016\/j.euroneuro.2012.01.008 (2012).","journal-title":"Eur Neuropsychopharmacol"},{"key":"31385_CR49","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/s00213-013-3243-1","volume":"231","author":"A Bahi","year":"2014","unstructured":"Bahi, A. & Dreyer, J. L. Chronic psychosocial stress causes delayed extinction and exacerbates reinstatement of ethanol-induced conditioned place preference in mice. Psychopharmacology (Berl) 231, 367\u2013377, https:\/\/doi.org\/10.1007\/s00213-013-3243-1 (2014).","journal-title":"Psychopharmacology (Berl)"},{"key":"31385_CR50","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-016-0747-8","volume":"13","author":"AA Tyrtyshnaia","year":"2016","unstructured":"Tyrtyshnaia, A. A. et al. Acute neuroinflammation provokes intracellular acidification in mouse hippocampus. Journal of neuroinflammation 13, 283, https:\/\/doi.org\/10.1186\/s12974-016-0747-8 (2016).","journal-title":"Journal of neuroinflammation"},{"key":"31385_CR51","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/j.tips.2011.01.003","volume":"32","author":"MB Passani","year":"2011","unstructured":"Passani, M. B. & Blandina, P. Histamine receptors in the CNS as targets for therapeutic intervention. Trends Pharmacol Sci 32, 242\u2013249, https:\/\/doi.org\/10.1016\/j.tips.2011.01.003 (2011).","journal-title":"Trends Pharmacol Sci"},{"key":"31385_CR52","doi-asserted-by":"crossref","unstructured":"Fox, G. B. et al. Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: II. Neurophysiological characterization and broad preclinical efficacy in cognition and schizophrenia of a potent and selective histamine H3 receptor antagonist. J Pharmacol Exp Ther 313, 176\u2013190, doi:jpet.104.078402 (2005).","DOI":"10.1124\/jpet.104.078402"},{"key":"31385_CR53","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/S0166-4328(01)00379-5","volume":"131","author":"GB Fox","year":"2002","unstructured":"Fox, G. B. et al. Effects of histamine H(3) receptor ligands GT-2331 and ciproxifan in a repeated acquisition avoidance response in the spontaneously hypertensive rat pup. Behav Brain Res 131, 151\u2013161 (2002).","journal-title":"Behav Brain Res"},{"key":"31385_CR54","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1016\/S0091-3057(02)00745-1","volume":"72","author":"GB Fox","year":"2002","unstructured":"Fox, G. B. et al. Differential in vivo effects of H3 receptor ligands in a new mouse dipsogenia model. Pharmacol Biochem Behav 72, 741\u2013750 (2002).","journal-title":"Pharmacol Biochem Behav"},{"issue":"Suppl 1","key":"31385_CR55","doi-asserted-by":"publisher","first-page":"S49","DOI":"10.1007\/s00011-003-0323-4","volume":"53","author":"GB Fox","year":"2004","unstructured":"Fox, G. B. et al. Cognition enhancing effects of novel H(3) receptor (H(3)R) antagonists in several animal models. Inflamm Res 53(Suppl 1), S49\u201350, https:\/\/doi.org\/10.1007\/s00011-003-0323-4 (2004).","journal-title":"Inflamm Res"},{"key":"31385_CR56","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1124\/jpet.102.047241","volume":"305","author":"GB Fox","year":"2003","unstructured":"Fox, G. B. et al. Two novel and selective nonimidazole H3 receptor antagonists A-304121 and A-317920: II. In vivo behavioral and neurophysiological characterization. J Pharmacol Exp Ther 305, 897\u2013908, https:\/\/doi.org\/10.1124\/jpet.102.047241 (2003).","journal-title":"J Pharmacol Exp Ther"},{"key":"31385_CR57","doi-asserted-by":"publisher","first-page":"709","DOI":"10.3389\/fphar.2017.00709","volume":"8","author":"A Alachkar","year":"2017","unstructured":"Alachkar, A., Lazewska, D., Kiec-Kononowicz, K. & Sadek, B. The Histamine H3 Receptor Antagonist E159 Reverses Memory Deficits Induced by Dizocilpine in Passive Avoidance and Novel Object Recognition Paradigm in Rats. Front Pharmacol 8, 709, https:\/\/doi.org\/10.3389\/fphar.2017.00709 (2017).","journal-title":"Front Pharmacol"},{"key":"31385_CR58","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1111\/j.1467-7687.2009.00882.x","volume":"13","author":"JS Noland","year":"2010","unstructured":"Noland, J. S., Steven Reznick, J., Stone, W. L., Walden, T. & Sheridan, E. H. Better working memory for non-social targets in infant siblings of children with Autism Spectrum Disorder. Dev Sci 13, 244\u2013251, https:\/\/doi.org\/10.1111\/j.1467-7687.2009.00882.x (2010).","journal-title":"Dev Sci"},{"key":"31385_CR59","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1124\/jpet.110.166876","volume":"336","author":"JD Brioni","year":"2011","unstructured":"Brioni, J. D., Esbenshade, T. A., Garrison, T. R., Bitner, S. R. & Cowart, M. D. Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer\u2019s disease. J Pharmacol Exp Ther 336, 38\u201346, https:\/\/doi.org\/10.1124\/jpet.110.166876 (2011).","journal-title":"J Pharmacol Exp Ther"},{"key":"31385_CR60","doi-asserted-by":"publisher","unstructured":"Zhao, H., Jiang, Y. H. & Zhang, Y. Q. Modeling autism in non-human primates: Opportunities and challenges. Autism Res, https:\/\/doi.org\/10.1002\/aur.1945 (2018).","DOI":"10.1002\/aur.1945"},{"key":"31385_CR61","doi-asserted-by":"publisher","first-page":"171","DOI":"10.3389\/fnins.2017.00171","volume":"11","author":"Z Peter","year":"2017","unstructured":"Peter, Z., Oliphant, M. E. & Fernandez, T. V. Motor Stereotypies: A Pathophysiological Review. Front Neurosci 11, 171, https:\/\/doi.org\/10.3389\/fnins.2017.00171 (2017).","journal-title":"Front Neurosci"},{"key":"31385_CR62","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/B978-0-12-411546-0.00006-8","volume":"112","author":"P Paschou","year":"2013","unstructured":"Paschou, P., Fernandez, T. V., Sharp, F., Heiman, G. A. & Hoekstra, P. J. Genetic susceptibility and neurotransmitters in Tourette syndrome. Int Rev Neurobiol 112, 155\u2013177, https:\/\/doi.org\/10.1016\/B978-0-12-411546-0.00006-8 (2013).","journal-title":"Int Rev Neurobiol"},{"key":"31385_CR63","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.pnpbp.2016.10.002","volume":"73","author":"M Rapanelli","year":"2017","unstructured":"Rapanelli, M. The magnificent two: histamine and the H3 receptor as key modulators of striatal circuitry. Prog Neuropsychopharmacol Biol Psychiatry 73, 36\u201340, https:\/\/doi.org\/10.1016\/j.pnpbp.2016.10.002 (2017).","journal-title":"Prog Neuropsychopharmacol Biol Psychiatry"},{"key":"31385_CR64","doi-asserted-by":"publisher","first-page":"21042","DOI":"10.1074\/jbc.M116.731406","volume":"291","author":"M Rapanelli","year":"2016","unstructured":"Rapanelli, M. et al. The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons. J Biol Chem 291, 21042\u201321052, https:\/\/doi.org\/10.1074\/jbc.M116.731406 (2016).","journal-title":"J Biol Chem"},{"key":"31385_CR65","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.neuropharm.2015.08.019","volume":"106","author":"M Rapanelli","year":"2016","unstructured":"Rapanelli, M. & Pittenger, C. Histamine and histamine receptors in Tourette syndrome and other neuropsychiatric conditions. Neuropharmacology 106, 85\u201390, https:\/\/doi.org\/10.1016\/j.neuropharm.2015.08.019 (2016).","journal-title":"Neuropharmacology"},{"key":"31385_CR66","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1007\/BF00176837","volume":"94","author":"F Borsini","year":"1988","unstructured":"Borsini, F. & Meli, A. Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology (Berl) 94, 147\u2013160 (1988).","journal-title":"Psychopharmacology (Berl)"},{"issue":"Suppl 2","key":"31385_CR67","doi-asserted-by":"publisher","first-page":"S16","DOI":"10.1038\/sj.mp.4001167","volume":"7","author":"DC Chugani","year":"2002","unstructured":"Chugani, D. C. Role of altered brain serotonin mechanisms in autism. Mol Psychiatry 7(Suppl 2), S16\u201317, https:\/\/doi.org\/10.1038\/sj.mp.4001167 (2002).","journal-title":"Mol Psychiatry"},{"key":"31385_CR68","doi-asserted-by":"publisher","first-page":"285","DOI":"10.5607\/en.2015.24.4.285","volume":"24","author":"DF Mabunga","year":"2015","unstructured":"Mabunga, D. F., Gonzales, E. L., Kim, J. W., Kim, K. C. & Shin, C. Y. Exploring the Validity of Valproic Acid Animal Model of Autism. Experimental neurobiology 24, 285\u2013300, https:\/\/doi.org\/10.5607\/en.2015.24.4.285 (2015).","journal-title":"Experimental neurobiology"},{"key":"31385_CR69","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.neulet.2008.01.066","volume":"434","author":"EV Orekhova","year":"2008","unstructured":"Orekhova, E. V. et al. Sensory gating in young children with autism: relation to age, IQ, and EEG gamma oscillations. Neurosci Lett 434, 218\u2013223, https:\/\/doi.org\/10.1016\/j.neulet.2008.01.066 (2008).","journal-title":"Neurosci Lett"},{"key":"31385_CR70","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1177\/1073858403253552","volume":"9","author":"MF Casanova","year":"2003","unstructured":"Casanova, M. F., Buxhoeveden, D. & Gomez, J. Disruption in the inhibitory architecture of the cell minicolumn: implications for autism. Neuroscientist 9, 496\u2013507, https:\/\/doi.org\/10.1177\/1073858403253552 (2003).","journal-title":"Neuroscientist"},{"key":"31385_CR71","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1034\/j.1601-183X.2003.00037.x","volume":"2","author":"JL Rubenstein","year":"2003","unstructured":"Rubenstein, J. L. & Merzenich, M. M. Model of autism: increased ratio of excitation\/inhibition in key neural systems. Genes Brain Behav 2, 255\u2013267 (2003).","journal-title":"Genes Brain Behav"},{"key":"31385_CR72","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1016\/j.bbadis.2016.12.016","volume":"1863","author":"S Barata-Antunes","year":"2017","unstructured":"Barata-Antunes, S., Cristovao, A. C., Pires, J., Rocha, S. M. & Bernardino, L. Dual role of histamine on microglia-induced neurodegeneration. Biochim Biophys Acta 1863, 764\u2013769, https:\/\/doi.org\/10.1016\/j.bbadis.2016.12.016 (2017).","journal-title":"Biochim Biophys Acta"},{"key":"31385_CR73","doi-asserted-by":"publisher","first-page":"321","DOI":"10.3389\/fnins.2016.00321","volume":"10","author":"H Javed","year":"2016","unstructured":"Javed, H., Azimullah, S., Haque, M. E. & Ojha, S. K. Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson\u2019s Disease. Front Neurosci 10, 321, https:\/\/doi.org\/10.3389\/fnins.2016.00321 (2016).","journal-title":"Front Neurosci"},{"key":"31385_CR74","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/S0021-9258(19)40252-4","volume":"265","author":"JP Thomas","year":"1990","unstructured":"Thomas, J. P., Maiorino, M., Ursini, F. & Girotti, A. W. Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. J Biol Chem 265, 454\u2013461 (1990).","journal-title":"J Biol Chem"},{"key":"31385_CR75","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1055\/s-0031-1301326","volume":"62","author":"D Mahmood","year":"2012","unstructured":"Mahmood, D., Khanam, R., Pillai, K. K. & Akhtar, M. Reversal of oxidative stress by histamine H(3) receptor-ligands in experimental models of schizophrenia. Arzneimittelforschung 62, 222\u2013229, https:\/\/doi.org\/10.1055\/s-0031-1301326 (2012).","journal-title":"Arzneimittelforschung"},{"key":"31385_CR76","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/S1734-1140(12)70746-6","volume":"64","author":"D Mahmood","year":"2012","unstructured":"Mahmood, D., Khanam, R., Pillai, K. K. & Akhtar, M. Protective effects of histamine H3-receptor ligands in schizophrenic behaviors in experimental models. Pharmacological reports: PR 64, 191\u2013204 (2012).","journal-title":"Pharmacological reports: PR"},{"key":"31385_CR77","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.neuropharm.2010.05.005","volume":"59","author":"F Jadidi-Niaragh","year":"2010","unstructured":"Jadidi-Niaragh, F. & Mirshafiey, A. Histamine and histamine receptors in pathogenesis and treatment of multiple sclerosis. Neuropharmacology 59, 180\u2013189, https:\/\/doi.org\/10.1016\/j.neuropharm.2010.05.005 (2010).","journal-title":"Neuropharmacology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-31385-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-31385-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-31385-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T08:55:54Z","timestamp":1671612954000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-31385-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,30]]},"references-count":77,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["31385"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-31385-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,30]]},"assertion":[{"value":"18 May 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 August 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"13077"}}