{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T20:58:34Z","timestamp":1785445114259,"version":"3.56.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100030902","name":"Martin-Luther-Universit\u00e4t Halle-Wittenberg","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100030902","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Naunyn-Schmiedeberg's Arch Pharmacol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Clozapine is one of the oldest antipsychotic drugs, the first atypical neuroleptic drug, and can be found in the World Health Organization\u2019s list of essential drugs. The precise mechanism of action of clozapine as an antipsychotic is not known. However, clozapine binds to many proteins in vitro. The objective of this study was to investigate the role of the dopamine D\n                    <jats:sub>1<\/jats:sub>\n                    receptor as a possible explanation for the cardiac side effects of clozapine. To this end, the hypothesis was tested that clozapine reduces the positive inotropic or positive chronotropic effects mediated by human cardiac dopamine D\n                    <jats:sub>1<\/jats:sub>\n                    receptors using a novel transgenic mouse model with cardiac myocyte-specific expression of the human dopamine D\n                    <jats:sub>1<\/jats:sub>\n                    receptor (D\n                    <jats:sub>1<\/jats:sub>\n                    -TG). The force of contraction in the left (LA) and right (RA) atria of adult D\n                    <jats:sub>1<\/jats:sub>\n                    -TG mice and, as a control, wild-type (WT) mice was measured and compared to human right atrial preparations (HAP), which were obtained from adult patients with coronary heart disease during cardiac surgery. In the presence of propranolol, which was used to block endogenous \u03b2-adrenoceptors, dopamine increased the force of contraction in LA and elevated the beating rate in RA from D\n                    <jats:sub>1<\/jats:sub>\n                    -TG. The effects in RA, but not in LA, were antagonized by clozapine. The effects were more pronounced in the presence of haloperidol, a typical antipsychotic drug. This drug was studied for comparison in mouse atrial preparations and was found to antagonize the effects of dopamine in both LA and RA. Furthermore, clozapine decreased dopamine receptor\u2013stimulated contractile force in HAP. These findings suggest that the D\n                    <jats:sub>1<\/jats:sub>\n                    receptor antagonism may contribute to cardiac side effects associated with clozapine in patients.\n                  <\/jats:p>","DOI":"10.1007\/s00210-026-05770-3","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T07:15:20Z","timestamp":1785395720000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clozapine acts as an antagonist of human dopamine D1 receptors in the atrium"],"prefix":"10.1007","author":[{"given":"Lina Maria","family":"Rayo Abella","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britt","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom Lars","family":"Neubert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6986-485X","authenticated-orcid":false,"given":"Ulrich","family":"Gergs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"5770_CR1","doi-asserted-by":"publisher","first-page":"4939","DOI":"10.1007\/s00210-023-02901-y","volume":"397","author":"LMR Abella","year":"2024","unstructured":"Abella LMR, Jacob H, Hesse C, Hofmann B, Schneider S, Schindler L, Keller M, Buchwalow IB, Jin C, Panula P, Dhein S, Klimas J, Hadova K, Gergs U, Neumann J (2024) Initial characterization of a transgenic mouse with overexpression of the human D1-dopamine receptor in the heart. Naunyn Schmiedebergs Arch Pharmacol 397:4939\u20134959. https:\/\/doi.org\/10.1007\/s00210-023-02901-y","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"5770_CR2","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1007\/s00210-011-0704-0","volume":"385","author":"H Appl","year":"2012","unstructured":"Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (2012) Interactions of recombinant human histamine H\u2081R, H\u2082R, H\u2083R, and H\u2084R receptors with 34 antidepressants and antipsychotics. Naunyn Schmiedebergs Arch Pharmacol 385:145\u2013170. https:\/\/doi.org\/10.1007\/s00210-011-0704-0","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"issue":"7428","key":"5770_CR3","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/nature11691","volume":"492","author":"J Besnard","year":"2012","unstructured":"Besnard J, Ruda GF, Setola V, Abecassis K, Rodriguiz RM, Huang XP, Norval S, Sassano MF, Shin AI, Webster LA, Simeons FR, Stojanovski L, Prat A, Seidah NG, Constam DB, Bickerton GR, Read KD, Wetsel WC, Gilbert IH, Roth BL, Hopkins AL (2012) Automated design of ligands to polypharmacological profiles. Nature 492(7428):215\u2013220. https:\/\/doi.org\/10.1038\/nature11691","journal-title":"Nature"},{"key":"5770_CR4","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2023.115336","volume":"326","author":"E Clapham","year":"2023","unstructured":"Clapham E, Reutfors J, Linder M, Brandt L, Sundstr\u00f6m J, Bod\u00e9n R (2023) The association between exposure to clozapine, olanzapine, and quetiapine and the outcomes perimyocarditis and heart failure: a population-based cohort study. Psychiatry Res 326:115336. https:\/\/doi.org\/10.1016\/j.psychres.2023.115336","journal-title":"Psychiatry Res"},{"key":"5770_CR5","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1177\/0957154X07070335","volume":"18","author":"J Crilly","year":"2007","unstructured":"Crilly J (2007) The history of clozapine and its emergence in the US market: a review and analysis. Hist Psychiatry 18:39\u201360. https:\/\/doi.org\/10.1177\/0957154X07070335","journal-title":"Hist Psychiatry"},{"key":"5770_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2022.108236","volume":"236","author":"A de Bartolomeis","year":"2022","unstructured":"de Bartolomeis A, Vellucci L, Barone A, Manchia M, de Luca V, Iasevoli F, Correll CU (2022) Clozapine\u2018s multiple cellular mechanisms: what do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophrenia. Pharmacol Ther 236:108236. https:\/\/doi.org\/10.1016\/j.pharmthera.2022.108236","journal-title":"Pharmacol Ther"},{"key":"5770_CR7","doi-asserted-by":"publisher","unstructured":"Filippis RD, Fazio PD (2026) The key to clozapine mystery may lie in its shape. Schizophr Bull 52. https:\/\/doi.org\/10.1093\/schbul\/sbag061","DOI":"10.1093\/schbul\/sbag061"},{"key":"5770_CR8","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1007\/s00210-008-0371-y","volume":"379","author":"U Gergs","year":"2009","unstructured":"Gergs U, Neumann J, Simm A, Silber R-E, Remmers FO, L\u00e4er S (2009) Phosphorylation of phospholamban and troponin I through 5-HT4 receptors in the isolated human atrium. Naunyn Schmiedebergs Arch Pharmacol 379:349\u2013359. https:\/\/doi.org\/10.1007\/s00210-008-0371-y","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"5770_CR9","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1007\/s00210-024-03340-z","volume":"398","author":"U Gergs","year":"2025","unstructured":"Gergs U, Pham TH, Rayo Abella LM, Hesse C, Grundig P, Dhein S, Hofmann B, Neumann J (2025) Contractile effects of stimulation of D1-dopamine receptors in the isolated human atrium. Naunyn Schmiedebergs Arch Pharmacol 398:1497\u20131508. https:\/\/doi.org\/10.1007\/s00210-024-03340-z","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"5770_CR10","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.777463","volume":"8","author":"M Huang","year":"2021","unstructured":"Huang M, Yang Z, Li Y, Lan H, Cyganek L, Yuecel G, Lang S, Bieback K, El-Battrawy I, Zhou X, Borggrefe M, Akin I (2021) Dopamine D1\/D5 receptor signaling is involved in arrhythmogenesis in the setting of Takotsubo cardiomyopathy. Front Cardiovasc Med 8:777463. https:\/\/doi.org\/10.3389\/fcvm.2021.777463","journal-title":"Front Cardiovasc Med"},{"key":"5770_CR11","doi-asserted-by":"publisher","first-page":"161","DOI":"10.2165\/00003088-199324020-00005","volume":"24","author":"MW Jann","year":"1993","unstructured":"Jann MW, Grimsley SR, Gray EC, Chang WH (1993) Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinet 24:161\u2013176. https:\/\/doi.org\/10.2165\/00003088-199324020-00005","journal-title":"Clin Pharmacokinet"},{"key":"5770_CR12","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.redox.2018.07.008","volume":"19","author":"X Jiang","year":"2018","unstructured":"Jiang X, Liu Y, Liu X, Wang W, Wang Z, Hu Y, Zhang Y, Zhang Y, Jose PA, Wei Q, Yang Z (2018) Over-expression of a cardiac-specific human dopamine D5 receptor mutation in mice causes a dilated cardiomyopathy through ROS over-generation by NADPH oxidase activation and Nrf2 degradation. Redox Biol 19:134\u2013146. https:\/\/doi.org\/10.1016\/j.redox.2018.07.008","journal-title":"Redox Biol"},{"key":"5770_CR13","doi-asserted-by":"publisher","first-page":"CD009830","DOI":"10.1002\/14651858.CD009830.pub2","volume":"11","author":"A Khushu","year":"2016","unstructured":"Khushu A, Powney MJ (2016) Haloperidol for long-term aggression in psychosis. Cochrane Database Syst Rev 11:CD009830. https:\/\/doi.org\/10.1002\/14651858.CD009830.pub2","journal-title":"Cochrane Database Syst Rev"},{"key":"5770_CR14","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1007\/s00277-020-04215-y","volume":"99","author":"A Mijovic","year":"2020","unstructured":"Mijovic A, MacCabe JH (2020) Clozapine-induced agranulocytosis. Ann Hematol 99:2477\u20132482. https:\/\/doi.org\/10.1007\/s00277-020-04215-y","journal-title":"Ann Hematol"},{"key":"5770_CR15","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.biopsych.2025.06.011","volume":"99","author":"RM Murray","year":"2026","unstructured":"Murray RM, Egerton A, Gao Y, Grace AA, Howes O, Jauhar S, Leucht S, Chen EYH, MacCabe JH, McCutcheon RA, Natesan S, Taylor D (2026) Why is clozapine uniquely effective in treatment-resistant schizophrenia? A review and proposal. Biol Psychiatry 99:517\u2013526. https:\/\/doi.org\/10.1016\/j.biopsych.2025.06.011","journal-title":"Biol Psychiatry"},{"key":"5770_CR16","doi-asserted-by":"publisher","unstructured":"National Academies Press (US) (2011) Guide for the care and use of laboratory animals, 8th edn., Washington (DC). https:\/\/doi.org\/10.17226\/12910","DOI":"10.17226\/12910"},{"key":"5770_CR17","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1006\/jmcc.1998.0760","volume":"30","author":"J Neumann","year":"1998","unstructured":"Neumann J, Boknik P, DePaoli-Roach AA, Field LJ, Rockman HA, Kobayashi YM, Kelley JS, Jones LR (1998) Targeted overexpression of phospholamban to mouse atrium depresses Ca2+ transport and contractility. J Mol Cell Cardiol 30:1991\u20132002. https:\/\/doi.org\/10.1006\/jmcc.1998.0760","journal-title":"J Mol Cell Cardiol"},{"key":"5770_CR18","doi-asserted-by":"publisher","unstructured":"Neumann J, Hofmann B, Dhein S, Gergs U (2023) Role of dopamine in the heart in health and disease. Int J Mol Sci 24. https:\/\/doi.org\/10.3390\/ijms24055042","DOI":"10.3390\/ijms24055042"},{"key":"5770_CR19","doi-asserted-by":"publisher","unstructured":"Neumann J, Schmidt F, Hofmann B, Gergs U (2025) Glucagon can increase force of contraction via glucagon receptors in the isolated human atrium. Int J Mol Sci 26. https:\/\/doi.org\/10.3390\/ijms26020698","DOI":"10.3390\/ijms26020698"},{"key":"5770_CR20","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1007\/s40263-017-0461-9","volume":"31","author":"KJ Ronaldson","year":"2017","unstructured":"Ronaldson KJ (2017) Cardiovascular disease in clozapine-treated patients: evidence, mechanisms and management. CNS Drugs 31:777\u2013795. https:\/\/doi.org\/10.1007\/s40263-017-0461-9","journal-title":"CNS Drugs"},{"key":"5770_CR21","unstructured":"Schlicht J, Hofmann B, Gergs U, Neumann J (2024) Haloperidol, clozapine and mirtazapine are functional antagonists at histamine receptors in human atrial preparations. In: European Histamine Research Society (ed) 51th Annual Meeting, p 50"},{"key":"5770_CR22","doi-asserted-by":"publisher","first-page":"6691","DOI":"10.1007\/s00210-024-03683-7","volume":"398","author":"JMA Schlicht","year":"2025","unstructured":"Schlicht JMA, Ahlrep U, Hofmann B, Kirchhefer U, Neumann J, Gergs U (2025) Clozapine is a functional antagonist at cardiac human H2-histamine receptors. Naunyn Schmiedebergs Arch Pharmacol 398:6691\u20136706. https:\/\/doi.org\/10.1007\/s00210-024-03683-7","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"5770_CR23","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.jphs.2016.05.012","volume":"131","author":"Y Shinoda","year":"2016","unstructured":"Shinoda Y, Tagashira H, Bhuiyan MS, Hasegawa H, Kanai H, Fukunaga K (2016) Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction. J Pharmacol Sci 131:172\u2013183. https:\/\/doi.org\/10.1016\/j.jphs.2016.05.012","journal-title":"J Pharmacol Sci"},{"key":"5770_CR24","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/0014-4886(91)90001-s","volume":"111","author":"JK Wamsley","year":"1991","unstructured":"Wamsley JK, Hunt ME, McQuade RD, Alburges ME (1991) 3HSCH39166, a D1 dopamine receptor antagonist: binding characteristics and localization. Exp Neurol 111:145\u2013151. https:\/\/doi.org\/10.1016\/0014-4886(91)90001-s","journal-title":"Exp Neurol"},{"key":"5770_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18128-x","volume":"11","author":"T Yamaguchi","year":"2020","unstructured":"Yamaguchi T, Sumida TS, Nomura S, Satoh M, Higo T, Ito M, Ko T, Fujita K, Sweet ME, Sanbe A, Yoshimi K, Manabe I, Sasaoka T, Taylor MRG, Toko H, Takimoto E, Naito AT, Komuro I (2020) Cardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure. Nat Commun 11:4364. https:\/\/doi.org\/10.1038\/s41467-020-18128-x","journal-title":"Nat Commun"}],"container-title":["Naunyn-Schmiedeberg's Archives of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00210-026-05770-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00210-026-05770-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00210-026-05770-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T20:04:42Z","timestamp":1785441882000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00210-026-05770-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":25,"alternative-id":["5770"],"URL":"https:\/\/doi.org\/10.1007\/s00210-026-05770-3","relation":{},"ISSN":["0028-1298","1432-1912"],"issn-type":[{"value":"0028-1298","type":"print"},{"value":"1432-1912","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]},"assertion":[{"value":"8 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Animals\n                      : The investigation conformed to the Guide for the Care and Use of Laboratory Animals as published by the National Research Council (2011). The animals were handled and maintained according to the approved protocols of the Animal Welfare Committee of the University of Halle-Wittenberg, Halle, Germany.\n                      Humans\n                      : This study complies with the Declaration of Helsinki and has been approved by the local ethics committee (hm-b\u00fc 04.08.2005).","order":1,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Informed consent was obtained from all patients included in the study.","order":2,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors declare that they have seen and approved the submitted version of this manuscript.","order":3,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}