{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:28:05Z","timestamp":1787066885325,"version":"build-2736575974"},"reference-count":103,"publisher":"Japanese Association for Laboratory Animal Science","issue":"1","funder":[{"name":"Ministry of Higher Education Malaysia for their financial support through the Fundamental Research Grant Scheme","award":["FRGS\/1\/2023\/SKK06\/"],"award-info":[{"award-number":["FRGS\/1\/2023\/SKK06\/"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Exp. Anim."],"published-print":{"date-parts":[[2026]]},"DOI":"10.1538\/expanim.25-0038","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T22:07:37Z","timestamp":1752703657000},"page":"23-39","source":"Crossref","is-referenced-by-count":1,"title":["Exploring the role of zolpidem in alleviating cognitive and motor impairments in chronic cerebral hypoperfusion: a rat model study with &lt;i&gt;in vivo&lt;\/i&gt; and &lt;i&gt;in silico&lt;\/i&gt; insights"],"prefix":"10.1538","volume":"75","author":[{"given":"Sherilyn M.T.","family":"Choo","sequence":"first","affiliation":[{"name":"Department of Neurosciences, School of Medical Sciences, Health Campus,              Universiti Sains Malaysia, Kubang Kerian, 16150 Kota Bharu, Kelantan,              Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatin H.","family":"Mohamad","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medical Sciences, Health Campus,              Universiti Sains Malaysia, Kubang Kerian, 16150 Kota Bharu, Kelantan,              Malaysia"},{"name":"Cytogenetics and Molecular Labs (CMDL), Premier Integrated Labs Sdn. Bhd,              Pantai Hospital Kuala Lumpur, Jalan Bukit Pantai, Bangsar, 59100 Kuala Lumpur,              Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syarifah Maisarah Sayed","family":"Mohamad","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medical Sciences, Health Campus,              Universiti Sains Malaysia, Kubang Kerian, 16150 Kota Bharu, Kelantan,              Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jafri Malin","family":"Abdullah","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medical Sciences, Health Campus,              Universiti Sains Malaysia, Kubang Kerian, 16150 Kota Bharu, Kelantan,              Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khairul Bariyyah Abd","family":"Halim","sequence":"additional","affiliation":[{"name":"Research Unit for Bioinformatics and Computational Biology (RUBIC),              Kulliyyah of Science, International Islamic University Malaysia, Jalan Sultan Ahmad              Shah, Bandar Indera Mahkota, 25200 Kuantan, Pahang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azzmer Azzar Abdul","family":"Hamid","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Kulliyyah of Science, International Islamic              University Malaysia, Jalan Sultan Ahmad Shah, Bandar Indera Mahkota, 25200 Kuantan,              Pahang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad Tarmizi","family":"Che Has","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, School of Medical Sciences, Health Campus,              Universiti Sains Malaysia, Kubang Kerian, 16150 Kota Bharu, Kelantan,              Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"439","reference":[{"key":"1","doi-asserted-by":"crossref","unstructured":"1. Monti              JM, Spence              DW, Buttoo              K,                Pandi-Perumal              SR. Zolpidem\u2019s            use for insomnia. Asian J Psychiatr. 2017;            25: 79\u201390.","DOI":"10.1016\/j.ajp.2016.10.006"},{"key":"2","doi-asserted-by":"crossref","unstructured":"2. Zhu              S, Sridhar              A, Teng              J, Howard              RJ, Lindahl              E, Hibbs              RE. Structural            and dynamic mechanisms of GABA<sub>A<\/sub> receptor modulators with opposing            activities. Nat Commun. 2022;            13: 4582.","DOI":"10.1038\/s41467-022-32212-4"},{"key":"3","doi-asserted-by":"crossref","unstructured":"3. Anderson              KE, Gifeisman              RI, Basting              JL, Harris              DJ, Rajan              AR, McCall              KL, et            al. High prescribing and state-level variation in            Z-drug use among Medicare patients. Pharmacopsychiatry.            2023; 56: 149\u2013153.","DOI":"10.1055\/a-2085-2299"},{"key":"4","doi-asserted-by":"publisher","unstructured":"4. Arnts              H, van Erp              WS, Boon              LI, Bosman              CA, Admiraal              MM, Schrantee              A, et            al. Awakening after a sleeping pill: Restoring            functional brain networks after severe brain injury.            Cortex. 2020; 132:            135\u2013146.","DOI":"10.1016\/j.cortex.2020.08.011"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5. Bomalaski              MN, Claflin              ES, Townsend              W, Peterson              MD. Zolpidem            for the treatment of neurologicdisorders: asystematic review.            JAMA Neurol. 2017; 74:            1130\u20131139.","DOI":"10.1001\/jamaneurol.2017.1133"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6. Wu              C, Sun              D. GABA            receptors in brain development, function, and injury. Metab            Brain Dis. 2015; 30:            367\u2013379.","DOI":"10.1007\/s11011-014-9560-1"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7. Georgiopoulos              M, Katsakiori              P,                Kefalopoulou              Z, Ellul              J, Chroni              E,                Constantoyannis              C. Vegetative            state and minimally conscious state: a review of the therapeutic            interventions. Stereotact Funct Neurosurg.            2010; 88: 199\u2013207.","DOI":"10.1159\/000314354"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8. Hahm              MH, Woo              J. Paradoxical            Motor and Cognitive Function Recovery in Response to Zolpidem in a Patient with            Hypoxic-ischemic Brain Injury: A Case Report. Clin            Psychopharmacol Neurosci. 2019; 17:            453\u2013457.","DOI":"10.9758\/cpn.2019.17.3.453"},{"key":"9","unstructured":"9. Thonnard              M, Gosseries              O, Demertzi              A, Lugo              Z,                Vanhaudenhuyse              A, Bruno              MA, et            al. Effect of zolpidem in chronic disorders of            consciousness: a prospective open-label study. Funct            Neurol. 2013; 28:            259\u2013264 https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC3951253\/."},{"key":"10","doi-asserted-by":"crossref","unstructured":"10. Oh              MK, Yoon              KJ, Lee              YT, Chae              SW, Choi              HY, Shin              HS, et            al. Effect of zolpidem on functional recovery in a            rat model of ischemic stroke. J Int Med Res.            2018; 46: 249\u2013257.","DOI":"10.1177\/0300060517723799"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11. Cherubini              E, Miles              R. The CA3            region of the hippocampus: how is it? What is it for? How does it do            it? Front Cell Neurosci. 2015;            9: 19.","DOI":"10.3389\/fncel.2015.00019"},{"key":"12","doi-asserted-by":"crossref","unstructured":"12. Xu              NZ, Ernst              M, Treven              M, Cerne              R, Wakulchik              M, Li              X, et            al. Negative allosteric modulation of alpha            5-containing GABA<sub>A<\/sub> receptors engenders antidepressant-like effects and            selectively prevents age-associated hyperactivity in tau-depositing          mice. Psychopharmacology (Berl). 2018;            235: 1151\u20131161.","DOI":"10.1007\/s00213-018-4832-9"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13. Mohamad              FH, Has              ATC. The            \u03b15-containing GABA<sub>A<\/sub> receptors: A brief summary. J Mol            Neurosci. 2019; 67:            343\u2013351.","DOI":"10.1007\/s12031-018-1246-4"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14. Ben-Ari              Y. Is the            awakening produced by benzodiazepines due to excitatory actions of            GABA? Transl Med Commun. 2021;            6: 6.","DOI":"10.1186\/s41231-021-00085-2"},{"key":"15","doi-asserted-by":"crossref","unstructured":"15. Che                Has              AT, Absalom              N, van                Nieuwenhuijzen              PS, Clarkson              AN, Ahring              PK, Chebib              M. Zolpidem is            a potent stoichiometry-selective modulator of \u03b11\u03b23 GABAA receptors: evidence of a novel            benzodiazepine site in the \u03b11-\u03b11 interface. Sci Rep.            2016; 6: 28674.","DOI":"10.1038\/srep28674"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16. Drexel              M, Puhakka              N, Kirchmair              E, H\u00f6rtnagl              H, Pitk\u00e4nen              A, Sperk              G. Expression            of GABA receptor subunits in the hippocampus and thalamus after experimental traumatic            brain injury. Neuropharmacology. 2015;            88: 122\u2013133.","DOI":"10.1016\/j.neuropharm.2014.08.023"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17. Fatemi              SH, Folsom              TD, Rooney              RJ, Thuras              PD. Expression            of GABAA \u03b12-, \u03b21- and \u03b5-receptors are altered significantly in the lateral cerebellum of            subjects with schizophrenia, major depression and bipolar disorder.            Transl Psychiatry. 2013; 3:            e303.","DOI":"10.1038\/tp.2013.64"},{"key":"18","doi-asserted-by":"crossref","unstructured":"18. Kharlamov              EA, Downey              KL, Jukkola              PI, Grayson              DR, Kelly              KM. Expression            of GABA A receptor alpha1 subunit mRNA and protein in rat neocortex following            photothrombotic infarction. Brain Res.            2008; 1210: 29\u201338.","DOI":"10.1016\/j.brainres.2008.02.070"},{"key":"19","doi-asserted-by":"crossref","unstructured":"19. Mtchedlishvili              Z,                Lepsveridze              E, Xu              H, Kharlamov              EA, Lu              B, Kelly              KM. Increase of            GABAA receptor-mediated tonic inhibition in dentate granule cells after traumatic brain            injury. Neurobiol Dis. 2010;            38: 464\u2013475.","DOI":"10.1016\/j.nbd.2010.03.012"},{"key":"20","doi-asserted-by":"crossref","unstructured":"20. Tossell              K, Dodhia              RA, Galet              B, Tkachuk              O, Ungless              MA. Tonic            GABAergic inhibition, via GABA<sub>A<\/sub> receptors containing \u03b1\u03b2\u0190 subunits, regulates            excitability of ventral tegmental area dopamine neurons. Eur J            Neurosci. 2021; 53:            1722\u20131737.","DOI":"10.1111\/ejn.15133"},{"key":"21","doi-asserted-by":"publisher","unstructured":"21. Davies              PA, Hanna              MC, Hales              TG, Kirkness              EF.            Insensitivity to anaesthetic agents conferred by a class of GABA(A)            receptor subunit. Nature. 1997;            385: 820\u2013823.","DOI":"10.1038\/385820a0"},{"key":"22","doi-asserted-by":"crossref","unstructured":"22. Whiting              PJ,                McAllister              G, Vassilatis              D, Bonnert              TP, Heavens              RP, Smith              DW, et            al. Neuronally restricted RNA splicing regulates the            expression of a novel GABAA receptor subunit conferring atypical functional properties            [corrected; erratum to be published]. J Neurosci.            1997; 17: 5027\u20135037.","DOI":"10.1523\/JNEUROSCI.17-13-05027.1997"},{"key":"23","doi-asserted-by":"crossref","unstructured":"23. Che                Has              AT, Hilyani                Mohamad              F, Othman              MZ. The            distinctive assembly pattern of \u03b5 subunit in ternary \u03b11\u03b23\u03b5 and binary \u03b23\u03b5 GABAA            receptors. J Cell Neurosci Oxid Stress.            2020; 11:          874\u2013884.","DOI":"10.37212\/jcnos.715215"},{"key":"24","doi-asserted-by":"crossref","unstructured":"24. Davies              PA, Kirkness              EF, Hales              TG. Evidence            for the formation of functionally distinct alphabetagammaepsilon GABA(A)            receptors. J Physiol. 2001;            537: 101\u2013113.","DOI":"10.1111\/j.1469-7793.2001.0101k.x"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25. Neelands              TR, Fisher              JL, Bianchi              M, Macdonald              RL. Spontaneous            and gamma-aminobutyric acid (GABA)-activated GABA(A) receptor channels formed by epsilon            subunit-containing isoforms. Mol Pharmacol.            1999; 55: 168\u2013178.","DOI":"10.1124\/mol.55.1.168"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26. Wagner              DA,                Goldschen-Ohm              MP, Hales              TG, Jones              MV. Kinetics            and spontaneous open probability conferred by the epsilon subunit of the GABAA            receptor. J Neurosci. 2005;            25: 10462\u201310468.","DOI":"10.1523\/JNEUROSCI.1658-05.2005"},{"key":"27","doi-asserted-by":"crossref","unstructured":"27. Le\u00f3n-Moreno              LC,                Casta\u00f1eda-Arellano              R,                Rivas-Carrillo              JD,                Due\u00f1as-Jim\u00e9nez              SH. Challenges            and Improvements of Developing an Ischemia Mouse Model Through Bilateral Common Carotid            Artery Occlusion. J Stroke Cerebrovasc Dis.            2020; 29: 104773.","DOI":"10.1016\/j.jstrokecerebrovasdis.2020.104773"},{"key":"28","doi-asserted-by":"crossref","unstructured":"28. Othman              MZ, Hassan              Z, Che Has              AT. Morris            water maze: a versatile and pertinent tool for assessing spatial learning and            memory. Exp Anim. 2022;            71: 264\u2013280. .","DOI":"10.1538\/expanim.21-0120"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29. Palpagama              TH, Sagniez              M, Kim              S, Waldvogel              HJ, Faull              RL, Kwakowsky              A.              GABA<sub>A<\/sub> Receptors Are Well Preserved in the Hippocampus of            Aged Mice. eNeuro. 2019;            6: 1\u201313.","DOI":"10.1523\/ENEURO.0496-18.2019"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30. Legesse              DH, Fan              C, Teng              J, Zhuang              Y, Howard              RJ, Noviello              CM, et            al. Structural insights into opposing actions of            neurosteroids on GABA<sub>A<\/sub> receptors. Nat          Commun. 2023; 14: 5091.","DOI":"10.1038\/s41467-023-40800-1"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31. Bollan              KA, Baur              R, Hales              TG, Sigel              E, Connolly              CN. The            promiscuous role of the epsilon subunit in GABAA receptor biogenesis.            Mol Cell Neurosci. 2008; 37:            610\u2013621.","DOI":"10.1016\/j.mcn.2007.12.011"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32. \u0160ali              A, Blundell              TL. Comparative            protein modelling by satisfaction of spatial restraints. J Mol            Biol. 1993; 234:            779\u2013815.","DOI":"10.1006\/jmbi.1993.1626"},{"key":"33","doi-asserted-by":"crossref","unstructured":"33. Elias              M, Liebschner              D, Koepke              J, Lecomte              C, Guillot              B, Jelsch              C, et            al. Hydrogen atoms in protein structures:            high-resolution X-ray diffraction structure of the DFPase. BMC            Res Notes. 2013; 6: 308.","DOI":"10.1186\/1756-0500-6-308"},{"key":"34","doi-asserted-by":"crossref","unstructured":"34. Morris              GM, Huey              R, Lindstrom              W, Sanner              MF, Belew              RK, Goodsell              DS, et            al. AutoDock4 and AutoDockTools4: Automated docking            with selective receptor flexibility. J Comput Chem.            2009; 30: 2785\u20132791.","DOI":"10.1002\/jcc.21256"},{"key":"35","unstructured":"35. DeLano              WL. PyMOL: An            open-source molecular graphics tool<i>.<\/i>CCP4            Newsletter on Protein Crystallography. 2002; 40:            82\u201392."},{"key":"36","doi-asserted-by":"crossref","unstructured":"36. Salentin              S, Schreiber              S, Haupt              VJ, Adasme              MF, Schroeder              M. PLIP: fully            automated protein-ligand interaction profiler. Nucleic Acids            Res. 2015; 43:(W1):          W443\u2013W447.","DOI":"10.1093\/nar\/gkv315"},{"key":"37","unstructured":"37. Dassault                Syst\u00e8mes              BIOVIA. (2016).          Discovery Studio Modeling Environment (Version 2016) [Software]. Dassault Syst\u00e8mes."},{"key":"38","doi-asserted-by":"crossref","unstructured":"38. Lindahl              E, Hess              B, van der                Spoel              D. GROMACS 3.0:            a package for molecular simulation and trajectory analysis. J            Mol Model. 2001; 7:            306\u2013317.","DOI":"10.1007\/s008940100045"},{"key":"39","doi-asserted-by":"crossref","unstructured":"39. Murlidaran              S, H\u00e9nin              J, Brannigan              G. Competitive            dewetting underlies site specific binding of general anesthetics to GABA(A)            receptors.bioRxiv. doi: https:\/\/doi.org\/10.1101\/694612,          July 8, 2019, preprint: not peer-reviewed.","DOI":"10.1101\/694612"},{"key":"40","doi-asserted-by":"crossref","unstructured":"40. Kurki              M, Poso              A, Bartos              P, Miettinen              MS. Structure            of POPC lipid bilayers in OPLS3e force field. J Chem Inf            Model. 2022; 62:            6462\u20136474.","DOI":"10.1021\/acs.jcim.2c00395"},{"key":"41","doi-asserted-by":"crossref","unstructured":"41. Shahane              G, Ding              W,                Palaiokostas              M, Orsi              M. Physical            properties of model biological lipid bilayers: insights from all-atom molecular dynamics            simulations. J Mol Model. 2019;            25: 76.","DOI":"10.1007\/s00894-019-3964-0"},{"key":"42","doi-asserted-by":"crossref","unstructured":"42. Brannigan              G, H\u00e9nin              J, Law              R, Eckenhoff              R, Klein              ML. Embedded            cholesterol in the nicotinic acetylcholine receptor. Proc Natl            Acad Sci USA. 2008; 105:            14418\u201314423.","DOI":"10.1073\/pnas.0803029105"},{"key":"43","doi-asserted-by":"crossref","unstructured":"43. Elsagh              A, Zare              K, Monajjemi              M. An            electrochemical study of POPC phospholipid bilayers in a cell membrane.            Orient J Chem. 2016; 32:            2585\u20132598.","DOI":"10.13005\/ojc\/320530"},{"key":"44","doi-asserted-by":"crossref","unstructured":"44. Janosi              L, Gorfe              AA. Simulating            POPC and POPC\/POPG bilayers: Conserved packing and altered surface            reactivity. J Chem Theory Comput. 2010;            6: 3267\u20133273.","DOI":"10.1021\/ct100381g"},{"key":"45","doi-asserted-by":"crossref","unstructured":"45. Jo              S, Kim              T, Iyer              VG, Im              W. CHARMM-GUI:            a web-based graphical user interface for CHARMM. J Comput            Chem. 2008; 29:            1859\u20131865.","DOI":"10.1002\/jcc.20945"},{"key":"46","doi-asserted-by":"crossref","unstructured":"46. Patodia              S, Bagaria              A, Chopra              D. Molecular            dynamics simulation of proteins: A brief overview. J Phys Chem            Biophys. 2014; 4:            1\u20134.","DOI":"10.4172\/2161-0398.1000166"},{"key":"47","doi-asserted-by":"crossref","unstructured":"47. Balkaya              M, Kr\u00f6ber              JM, Rex              A, Endres              M. Assessing            post-stroke behavior in mouse models of focal ischemia. J Cereb            Blood Flow Metab. 2013; 33:            330\u2013338.","DOI":"10.1038\/jcbfm.2012.185"},{"key":"48","doi-asserted-by":"crossref","unstructured":"48. Kleywegt              GJ, Jones              TA.            Phi\/psi-chology: Ramachandran revisited.            Structure. 1996; 4:            1395\u20131400.","DOI":"10.1016\/S0969-2126(96)00147-5"},{"key":"49","doi-asserted-by":"crossref","unstructured":"49. Wlodawer              A.            Stereochemistry and validation of macromolecular            structures. Methods Mol Biol. 2017;            1607: 595\u2013610.","DOI":"10.1007\/978-1-4939-7000-1_24"},{"key":"50","doi-asserted-by":"crossref","unstructured":"50. Vijayan              RSK,                Bhattacharyya              D, Ghoshal              N. Deciphering            the binding mode of Zolpidem to GABA(A) \u03b1<sub>1<\/sub> receptor - insights from molecular            dynamics simulation. J Mol Model. 2012;            18: 1345\u20131354.","DOI":"10.1007\/s00894-011-1142-0"},{"key":"51","doi-asserted-by":"crossref","unstructured":"51. Sneha              P, Doss              CGP. (2016).          Molecular dynamics: New frontier in personalized medicine. In R. Donev (Ed.),            <i>Advances in Protein Chemistry and Structural Biology<\/i> (Vol. 102, pp.          181\u2013224). Academic Press. .","DOI":"10.1016\/bs.apcsb.2015.09.004"},{"key":"52","doi-asserted-by":"crossref","unstructured":"52. Wang              X, Yang              X, Han              F, Gao              L, Zhou              Y. Propofol            improves brain injury induced by chronic cerebral hypoperfusion in rats.            Food Sci Nutr. 2021; 9:            2801\u20132809.","DOI":"10.1002\/fsn3.1915"},{"key":"53","doi-asserted-by":"crossref","unstructured":"53. Otori              T, Katsumata              T, Muramatsu              H, Kashiwagi              F, Katayama              Y, Terashi              A. Long-term            measurement of cerebral blood flow and metabolism in a rat chronic hypoperfusion            model. Clin Exp Pharmacol Physiol. 2003;            30: 266\u2013272.","DOI":"10.1046\/j.1440-1681.2003.03825.x"},{"key":"54","doi-asserted-by":"crossref","unstructured":"54. Seibenhener              ML, Wooten              MC. Use of the            Open Field Maze to measure locomotor and anxiety-like behavior in mice.            J Vis Exp. 2015; 96:            e52434.","DOI":"10.3791\/52434-v"},{"key":"55","doi-asserted-by":"crossref","unstructured":"55. Zimcikova              E, Simko              J, Karesova              I, Kremlacek              J, Malakova              J. Behavioral            effects of antiepileptic drugs in rats: Are the effects on mood and behavior detectable            in open-field test? Seizure. 2017;            52: 35\u201340.","DOI":"10.1016\/j.seizure.2017.09.015"},{"key":"56","doi-asserted-by":"crossref","unstructured":"56. Zhao              Y, Gu              JH, Dai              CL, Liu              Q, Iqbal              K, Liu              F, et            al. Chronic cerebral hypoperfusion causes decrease            of O-GlcNAcylation, hyperphosphorylation of tau and behavioral deficits in            mice. Front Aging Neurosci. 2014;            6: 10.","DOI":"10.3389\/fnagi.2014.00010"},{"key":"57","doi-asserted-by":"crossref","unstructured":"57. Prut              L, Belzung              C. The open            field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a            review. Eur J Pharmacol. 2003;            463: 3\u201333.","DOI":"10.1016\/S0014-2999(03)01272-X"},{"key":"58","doi-asserted-by":"crossref","unstructured":"58. Kadam              SD,                Mulholland              JD, Smith              DR, Johnston              MV, Comi              AM. Chronic            brain injury and behavioral impairments in a mouse model of term neonatal            strokes. Behav Brain Res. 2009;            197: 77\u201383.","DOI":"10.1016\/j.bbr.2008.08.003"},{"key":"59","doi-asserted-by":"crossref","unstructured":"59. Trenque              T, Bustany              P, Lamiable              D, Legros              S, Choisy              H.            Pharmacokinetics and brain distribution of zolpidem in the rat after            acute and chronic administration. J Pharm Pharmacol.            1993; 1982: 611\u2013613.","DOI":"10.1111\/j.2042-7158.1994.tb03868.x"},{"key":"60","doi-asserted-by":"crossref","unstructured":"60. Murphy              HM,                Ihekoronze              C, Wideman              CH.            Zolpidem-induced changes in activity, metabolism, and anxiety in            rats. Pharmacol Biochem Behav. 2011;            98: 81\u201386.","DOI":"10.1016\/j.pbb.2010.12.012"},{"key":"61","doi-asserted-by":"crossref","unstructured":"61. Farkas              E, Luiten              PGM, Bari              F. Permanent,            bilateral common carotid artery occlusion in the rat: a model for chronic cerebral            hypoperfusion-related neurodegenerative diseases. Brain Res            Brain Res Rev. 2007; 54:            162\u2013180.","DOI":"10.1016\/j.brainresrev.2007.01.003"},{"key":"62","doi-asserted-by":"crossref","unstructured":"62. Clark              RE, Broadbent              NJ, Squire              LR. The            hippocampus and spatial memory: findings with a novel modification of the water            maze. J Neurosci. 2007;            27: 6647\u20136654.","DOI":"10.1523\/JNEUROSCI.0913-07.2007"},{"key":"63","doi-asserted-by":"crossref","unstructured":"63. Nikonenko              AG, Radenovic              L, Andjus              PR, Skibo              GG. Structural            features of ischemic damage in the hippocampus. Anat Rec            (Hoboken). 2009; 292:            1914\u20131921.","DOI":"10.1002\/ar.20969"},{"key":"64","doi-asserted-by":"crossref","unstructured":"64. Farkas              E, Instit\u00f3ris              A, Domoki              F, Mih\u00e1ly              A, Bari              F. The effect            of pre- and posttreatment with diazoxide on the early phase of chronic cerebral            hypoperfusion in the rat. Brain Res. 2006;            1087: 168\u2013174.","DOI":"10.1016\/j.brainres.2006.02.134"},{"key":"65","doi-asserted-by":"crossref","unstructured":"65. Liu              H, Zhang              J. Cerebral            hypoperfusion and cognitive impairment: the pathogenic role of vascular oxidative            stress. Int J Neurosci. 2012;            122: 494\u2013499.","DOI":"10.3109\/00207454.2012.686543"},{"key":"66","doi-asserted-by":"crossref","unstructured":"66. Vorhees              CV, Williams              MT. Assessing            spatial learning and memory in rodents. ILAR J.            2014; 55: 310\u2013332.","DOI":"10.1093\/ilar\/ilu013"},{"key":"67","doi-asserted-by":"crossref","unstructured":"67. Clauss              R, Sathekge              M, Nel              W. Transient            improvement of spinocerebellar ataxia with zolpidem. N Engl J            Med. 2004; 351:            511\u2013512.","DOI":"10.1056\/NEJM200407293510522"},{"key":"68","doi-asserted-by":"crossref","unstructured":"68. Cohen              SI, Duong              TT. Increased            arousal in a patient with anoxic brain injury after administration of            zolpidem. Am J Phys Med Rehabil. 2008;            87: 229\u2013231.","DOI":"10.1097\/PHM.0b013e318161971b"},{"key":"69","doi-asserted-by":"crossref","unstructured":"69. Whiting              PJ.              GABA-<sub>A<\/sub> receptor subtypes in the brain: a paradigm for CNS            drug discovery? Drug Discov Today. 2003;            8: 445\u2013450.","DOI":"10.1016\/S1359-6446(03)02703-X"},{"key":"70","doi-asserted-by":"crossref","unstructured":"70. Maksay              G, Thompson              SA, Wafford              KA. The            pharmacology of spontaneously open alpha 1 beta 3 epsilon GABA A            receptor-ionophores. Neuropharmacology.            2003; 44: 994\u20131002.","DOI":"10.1016\/S0028-3908(03)00116-3"},{"key":"71","doi-asserted-by":"crossref","unstructured":"71. Kasparov              S, Davies              KA, Patel              UA, Boscan              P, Garret              M, Paton              JFR. GABA(A)            receptor epsilon-subunit may confer benzodiazepine insensitivity to the caudal aspect of            the nucleus tractus solitarii of the rat. J Physiol.            2001; 536: 785\u2013796.","DOI":"10.1111\/j.1469-7793.2001.00785.x"},{"key":"72","doi-asserted-by":"crossref","unstructured":"72. Williams              ST, Conte              MM, Goldfine              AM, Noirhomme              Q, Gosseries              O, Thonnard              M, et            al. Common resting brain dynamics indicate a            possible mechanism underlying zolpidem response in severe brain injury.            eLife. 2013; 2: e01157.","DOI":"10.7554\/eLife.01157"},{"key":"73","doi-asserted-by":"crossref","unstructured":"73. Yu              X, Li              W, Ma              Y, Tossell              K, Harris              JJ, Harding              EC, et            al. GABA and glutamate neurons in the VTA regulate            sleep and wakefulness. Nat Neurosci. 2019;            22: 106\u2013119.","DOI":"10.1038\/s41593-018-0288-9"},{"key":"74","doi-asserted-by":"crossref","unstructured":"74. Ranna              M, Sinkkonen              ST, M\u00f6ykkynen              T,                Uusi-Oukari              M, Korpi              ER. Impact of \u03b5            and \u03b8 subunits on pharmacological properties of \u03b13\u03b21 GABAA receptors expressed in              <i>Xenopus<\/i> oocytes. BMC Pharmacol.            2006; 6: 1.","DOI":"10.1186\/1471-2210-6-1"},{"key":"75","doi-asserted-by":"crossref","unstructured":"75. Bartsch              T, D\u00f6hring              J, Rohr              A, Jansen              O, Deuschl              G. CA1 neurons            in the human hippocampus are critical for autobiographical memory, mental time travel,            and autonoetic consciousness. Proc Natl Acad Sci USA.            2011; 108: 17562\u201317567.","DOI":"10.1073\/pnas.1110266108"},{"key":"76","doi-asserted-by":"crossref","unstructured":"76. Buhr              A, Baur              R, Sigel              E. Subtle            changes in residue 77 of the gamma subunit of alpha1beta2gamma2 GABAA receptors            drastically alter the affinity for ligands of the benzodiazepine binding            site. J Biol Chem. 1997;            272: 11799\u201311804.","DOI":"10.1074\/jbc.272.18.11799"},{"key":"77","doi-asserted-by":"crossref","unstructured":"77. Renard              S, Olivier              A, Granger              P, Avenet              P, Graham              D, Sevrin              M, et            al. Structural elements of the gamma-aminobutyric            acid type A receptor conferring subtype selectivity for benzodiazepine site            ligands. J Biol Chem. 1999;            274: 13370\u201313374.","DOI":"10.1074\/jbc.274.19.13370"},{"key":"78","doi-asserted-by":"crossref","unstructured":"78. Sancar              F, Ericksen              SS, Kucken              AM, Teiss\u00e9re              JA,                Czajkowski              C. Structural            determinants for high-affinity zolpidem binding to GABA-A receptors.            Mol Pharmacol. 2007; 71:            38\u201346.","DOI":"10.1124\/mol.106.029595"},{"key":"79","doi-asserted-by":"crossref","unstructured":"79. Wingrove              PB, Thompson              SA, Wafford              KA, Whiting              PJ. Key amino            acids in the \u03b3 subunit of the \u03b3-aminobutyric acidA receptor that determine ligand            binding and modulation at the benzodiazepine site. Mol            Pharmacol. 1997; 52:            874\u2013881.","DOI":"10.1124\/mol.52.5.874"},{"key":"80","doi-asserted-by":"crossref","unstructured":"80. Hanson              SM, Morlock              EV, Satyshur              KA,                Czajkowski              C. Structural            requirements for eszopiclone and zolpidem binding to the gamma-aminobutyric acid type-A            (GABAA) receptor are different. J Med Chem.            2008; 51: 7243\u20137252.","DOI":"10.1021\/jm800889m"},{"key":"81","doi-asserted-by":"crossref","unstructured":"81. Xie              HB, Sha              Y, Wang              J, Cheng              MS. Some            insights into the binding mechanism of the GABAA receptor: a combined docking and            MM-GBSA study. J Mol Model. 2013;            19: 5489\u20135500.","DOI":"10.1007\/s00894-013-2049-8"},{"key":"82","doi-asserted-by":"publisher","unstructured":"82. Szarecka              A, Xu              Y, Tang              P. Dynamics of            heteropentameric nicotinic acetylcholine receptor: implications of the gating            mechanism. Proteins. 2007;            68: 948\u2013960.","DOI":"10.1002\/prot.21462"},{"key":"83","doi-asserted-by":"crossref","unstructured":"83. Hanson              SM,                Czajkowski              C. Structural            mechanisms underlying benzodiazepine modulation of the GABA(A) receptor.            J Neurosci. 2008; 28:            3490\u20133499.","DOI":"10.1523\/JNEUROSCI.5727-07.2008"},{"key":"84","doi-asserted-by":"crossref","unstructured":"84. Khatri              A, Weiss              DS. The role of            Loop F in the activation of the GABA receptor. J            Physiol. 2010; 588:            59\u201366.","DOI":"10.1113\/jphysiol.2009.179705"},{"key":"85","doi-asserted-by":"publisher","unstructured":"85. Zhu              S, Noviello              CM, Teng              J, Walsh              RM              Jr, Kim              JJ, Hibbs              RE. Structure            of a human synaptic GABA<sub>A<\/sub> receptor. Nature.            2018; 559: 67\u201372.","DOI":"10.1038\/s41586-018-0255-3"},{"key":"86","doi-asserted-by":"crossref","unstructured":"86. Bukanova              JV,                Kondratenko              RV, Solntseva              EI. Positive            allosteric modulators of GABA<sub>A<\/sub> receptor restore chloride current from            blockade by competitive antagonists in a ligand-dependent manner.            J Steroid Biochem Mol Biol. 2022; 224:            106158.","DOI":"10.1016\/j.jsbmb.2022.106158"},{"key":"87","doi-asserted-by":"crossref","unstructured":"87. Buhr              A, Schaerer              MT, Baur              R, Sigel              E. Residues at            positions 206 and 209 of the alpha1 subunit of gamma-aminobutyric AcidA receptors            influence affinities for benzodiazepine binding site ligands.            Mol Pharmacol. 1997;          52: 676\u2013682.","DOI":"10.1124\/mol.52.4.676"},{"key":"88","doi-asserted-by":"crossref","unstructured":"88. Wongsamitkul              N, Maldifassi              MC, Simeone              X, Baur              R, Ernst              M, Sigel              E. \u03b1 subunits            in GABA<sub>A<\/sub> receptors are dispensable for GABA and diazepam            action. Sci Rep. 2017; 7:            15498.","DOI":"10.1038\/s41598-017-15628-7"},{"key":"89","doi-asserted-by":"crossref","unstructured":"89. Richter              L, de Graaf              C, Sieghart              W, Varagic              Z, M\u00f6rzinger              M, de Esch              IJP, et            al. Diazepam-bound GABAA receptor models identify            new benzodiazepine binding-site ligands. Nat Chem Biol.            2012; 8: 455\u2013464.","DOI":"10.1038\/nchembio.917"},{"key":"90","doi-asserted-by":"crossref","unstructured":"90. Crestani              F, Assandri              R, T\u00e4uber              M, Martin              JR, Rudolph              U. Contribution            of the alpha1-GABA(A) receptor subtype to the pharmacological actions of benzodiazepine            site inverse agonists. Neuropharmacology.            2002; 43: 679\u2013684.","DOI":"10.1016\/S0028-3908(02)00159-4"},{"key":"91","doi-asserted-by":"crossref","first-page":"e42166","DOI":"10.7554\/eLife.42166","volume":"7","year":"2018","unstructured":"91. Zivanov              J, Nakane              T, Forsberg              BO, Kimanius              D, Hagen              WJ, Lindahl              E, et            al. New tools for automated high-resolution cryo-EM            structure determination in RELION-3. eLife.            2018; 7: e42166.","journal-title":"eLife","ISSN":"https:\/\/id.crossref.org\/issn\/2050-084X","issn-type":"print"},{"key":"92","doi-asserted-by":"crossref","unstructured":"92. Mohamad              FH, Mohamad                Jamali              MA, Che Has              AT.            Structure-function Studies of GABA(A) Receptors and Related            computer-aided Studies. J Mol Neurosci.            2023; 73: 804\u2013817.","DOI":"10.1007\/s12031-023-02158-3"},{"key":"93","doi-asserted-by":"crossref","unstructured":"93. Cao              AM, Quast              RB, Fatemi              F, Rondard              P, Pin              JP, Margeat              E. Allosteric            modulators enhance agonist efficacy by increasing the residence time of a GPCR in the            active state. Nat Commun. 2021;            12: 5426.","DOI":"10.1038\/s41467-021-25620-5"},{"key":"94","doi-asserted-by":"crossref","unstructured":"94. Kasaragod              VB, Mortensen              M, Hardwick              SW, Wahid              AA, Dorovykh              V, Chirgadze              DY, et            al. Mechanisms of inhibition and activation of            extrasynaptic \u03b1\u03b2 GABA<sub>A<\/sub> receptors. Nature.            2022; 602: 529\u2013533.","DOI":"10.1038\/s41586-022-04402-z"},{"key":"95","doi-asserted-by":"publisher","unstructured":"95. Kim              JJ, Gharpure              A, Teng              J, Zhuang              Y, Howard              RJ, Zhu              S, et            al. Shared structural mechanisms of general            anaesthetics and benzodiazepines. Nature.            2020; 585: 303\u2013308.","DOI":"10.1038\/s41586-020-2654-5"},{"key":"96","doi-asserted-by":"crossref","unstructured":"96. Kim              JJ, Hibbs              RE. Direct            structural insights into GABAA receptor pharmacology. Trends            Biochem Sci. 2021; 46:            502\u2013517.","DOI":"10.1016\/j.tibs.2021.01.011"},{"key":"97","doi-asserted-by":"publisher","unstructured":"97. Masiulis              S, Desai              R, Ucha\u0144ski              T, Serna                Martin              I, Laverty              D, Karia              D, et              al. GABA<sub>A<\/sub> receptor signalling            mechanisms revealed by structural pharmacology. Nature.            2019; 565: 454\u2013459.","DOI":"10.1038\/s41586-018-0832-5"},{"key":"98","doi-asserted-by":"crossref","unstructured":"98. Berg              KA, Clarke              WP. Making            sense of pharmacology: Inverse agonism and functional selectivity.            Int J Neuropsychopharmacol. 2018; 21:            962\u2013977.","DOI":"10.1093\/ijnp\/pyy071"},{"key":"99","doi-asserted-by":"crossref","unstructured":"99. Arthur              DE, Uzairu              A. Molecular            docking studies on the interaction of NCI anticancer analogues with human            Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit.            J King Saud Univ Sci. 2019; 31:            1151\u20131166.","DOI":"10.1016\/j.jksus.2019.01.011"},{"key":"100","doi-asserted-by":"crossref","unstructured":"100. Baumann              SW, Baur              R, Sigel              E. Individual            properties of the two functional agonist sites in GABA (A) receptors.            J Neurosci. 2003; 23:            11158\u201311166.","DOI":"10.1523\/JNEUROSCI.23-35-11158.2003"},{"key":"101","doi-asserted-by":"crossref","unstructured":"101. R\u00fcsch              D, Forman              SA. Classic            benzodiazepines modulate the open\u2013close equilibrium in              \u03b1<sup>1<\/sup>\u03b2<sup>2<\/sup>\u03b3<sup>2L<\/sup> \u03b3-aminobutyric acid type A            receptors. Anesthesiology. 2005;            102: 783\u2013792.","DOI":"10.1097\/00000542-200504000-00014"},{"key":"102","doi-asserted-by":"crossref","unstructured":"102. Schiff              ND. Recovery of            consciousness after brain injury: a mesocircuit hypothesis.            Trends Neurosci. 2010; 33:            1\u20139.","DOI":"10.1016\/j.tins.2009.11.002"},{"key":"103","doi-asserted-by":"crossref","unstructured":"103. Othman              MZ, Mohd                Nasir              MH, Wan Ahmad              WAN, Abdullah              JM, Che Has              AT.            Differential regulation of K<sup>+<\/sup>-Cl<sup>-<\/sup> cotransporter 2            (KCC2) and Na<sup>+<\/sup>-K<sup>+<\/sup>-Cl<sup>-<\/sup> cotransporter 1 (NKCC1)            expression by zolpidem in CA1 and CA3 hippocampal subregions of the lithium-pilocarpine            status epilepticus rat model. Exp Anim.            2025; 74: 286\u2013299.","DOI":"10.1538\/expanim.24-0120"}],"container-title":["Experimental Animals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/expanim\/75\/1\/75_25-0038\/_pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T04:14:16Z","timestamp":1767413656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jstage.jst.go.jp\/article\/expanim\/75\/1\/75_25-0038\/_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":103,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.1538\/expanim.25-0038","relation":{},"ISSN":["1341-1357","1881-7122"],"issn-type":[{"value":"1341-1357","type":"print"},{"value":"1881-7122","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026]]},"article-number":"25-0038"}}