{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:34:19Z","timestamp":1789616059656,"version":"build-2803163510"},"reference-count":109,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Szeged Open Access Fund","award":["7731"],"award-info":[{"award-number":["7731"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The limited efficacy of antipsychotics in treating the negative and cognitive symptoms of schizophrenia has prompted the exploration of adjuvant therapies. Several drugs developed for other indications\u2014including caffeine, metformin, and furosemide\u2014have shown procognitive potential. This study evaluated the effects of these agents on behavioral parameters using the reward-based Ambitus test, and on the cerebral D2 dopamine receptor (D2R) expression and binding. The drugs were administered individually and in combination in a schizophrenia-like triple-hit animal model (Lisket rats), derived from the Long Evans (LE) strain. Lisket rats received 14 days of drug treatment via drinking water; water-drinking LE rats served as the controls. The Ambitus test was conducted before treatment and on days 11\u201314. Caffeine enhanced activity without affecting learning or memory. Metformin and furosemide reduced exploratory behavior but improved reference memory; these effects were inhibited by caffeine co-administration. Although no statistically significant behavioral differences were found compared to water-treated Lisket rats, a trend toward reduced exploratory visits was observed in the triple-combination group. Lisket rats exhibited moderately reduced D2R binding in the cortex and increased binding in the hippocampus. Caffeine alone and in combination enhanced hippocampal D2R binding, while furosemide increased cortical D2R expression. This study is the first to highlight the behavioral and molecular effects of these non-antipsychotic agents in a schizophrenia model, supporting their potential for adjunctive use.<\/jats:p>","DOI":"10.3390\/ijms26136019","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T09:08:44Z","timestamp":1750669724000},"page":"6019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Repurposing Caffeine, Metformin, and Furosemide to Target Schizophrenia-Related Impairments in a Triple-Hit Rat Model"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6025-4577","authenticated-orcid":false,"given":"Gyongyi","family":"Horvath","sequence":"first","affiliation":[{"name":"Department of Physiology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, D\u00f3m t\u00e9r 10, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szonja Bianka","family":"Plesz","sequence":"additional","affiliation":[{"name":"Department of Physiology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, D\u00f3m t\u00e9r 10, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eszter","family":"Ducza","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorottya","family":"Varga","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edina","family":"Szucs","sequence":"additional","affiliation":[{"name":"Delta Bio2000 Kft., H-6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2235-5334","authenticated-orcid":false,"given":"S\u00e1ndor","family":"Benyhe","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, HUN-REN Biological Research Centre, H-6726 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leatitia Gabriella","family":"Adlan","sequence":"additional","affiliation":[{"name":"Department of Physiology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, D\u00f3m t\u00e9r 10, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabor","family":"Braunitzer","sequence":"additional","affiliation":[{"name":"Szt\u00e1rai Institute, University of Tokaj, H-3950 S\u00e1rospatak, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0185-2155","authenticated-orcid":false,"given":"Gabriella","family":"Kekesi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, D\u00f3m t\u00e9r 10, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1093\/schbul\/sbm074","article-title":"Molecular Targets for Treating Cognitive Dysfunction in Schizophrenia","volume":"33","author":"Gray","year":"2007","journal-title":"Schizophr. 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