{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T07:06:05Z","timestamp":1779692765947,"version":"3.53.1"},"reference-count":31,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T00:00:00Z","timestamp":1772755200000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100007132","name":"Otsuka Pharmaceutical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007132","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropsychopharm Rep"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Reduction of alcohol consumption is one of treatment goals to reduce harm among individuals with alcohol use disorder (AUD), a major worldwide health problem, for which nalmefene, an opioid receptor modulator, is used. In this study, the effect of nalmefene on ethanol (EtOH) intake, already reported, was evaluated in Wistar rats, as validation. In addition, effects of brexpiprazole, serotonin\u2013dopamine activity modulator, alone and in combination with nalmefene were evaluated to investigate further treatment option for AUD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>During the first training phase, animals had 10% EtOH as the only drinking fluid available for the first 5\u2009days. Then, the animals had a 24\u2010h free choice between EtOH and water for 39\u2009days which is named the continual access paradigm. Thereafter, the limited access paradigm, which restricted the availability of 10% EtOH to 1\u2009h every day, was carried out for 114\u2009days. EtOH intake (g\/kg\/1\u2009h) was determined by weighing 10% EtOH bottles before and after the limited EtOH access every day. Brexpiprazole (0.01\u20130.1\u2009mg\/kg, orally) and nalmefene (0.04\u20130.4\u2009mg\/kg, subcutaneously) were daily administered to rats 1\u2009h or 20\u2009min before starting the limited access paradigm for consecutive 4\u2009days, respectively. The combination effect was evaluated using each subeffective dose of brexpiprazole and nalmefene which did not significantly reduce EtOH intake. The daily and the average EtOH intake for 4\u2009days before and during the treatment with test compounds were statistically analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Brexpiprazole (0.1\u2009mg\/kg) and nalmefene (0.4\u2009mg\/kg) alone significantly decreased EtOH intake. Moreover, the combination of subeffective doses of brexpiprazole (0.01\u2009mg\/kg) and nalmefene (0.04\u2009mg\/kg) significantly and synergistically decreased EtOH intake.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These data suggest that brexpiprazole may have the potential to decrease alcohol intake in AUD patients. In addition, brexpiprazole may have a synergistic therapeutic effect with nalmefene in those patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/npr2.70107","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T23:37:48Z","timestamp":1773013068000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synergistic Effect of Combination Treatment of Brexpiprazole and Nalmefene on Ethanol Intake in Rats"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9625-6240","authenticated-orcid":false,"given":"Naoki","family":"Amada","sequence":"first","affiliation":[{"name":"Department of CNS Research, Tokushima Research Center for Drug Discovery Otsuka Pharmaceutical Co. Ltd.  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of CNS Research, Tokushima Research Center for Drug Discovery Otsuka Pharmaceutical Co. Ltd.  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Ohgi","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease Research, Osaka Research Center for Drug Discovery Otsuka Pharmaceutical Co. Ltd.  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Kakumoto","sequence":"additional","affiliation":[{"name":"Department of Lead Discovery Research Otsuka Pharmaceutical Co. Ltd.  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikio","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of CNS Research, Tokushima Research Center for Drug Discovery Otsuka Pharmaceutical Co. Ltd.  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Futamura","sequence":"additional","affiliation":[{"name":"Department of CNS Research, Tokushima Research Center for Drug Discovery Otsuka Pharmaceutical Co. Ltd.  Tokushima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Maeda","sequence":"additional","affiliation":[{"name":"CNS Group, Medical Affairs Department Otsuka Pharmaceutical Co. Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,6]]},"reference":[{"key":"e_1_2_13_2_1","unstructured":"WHO \u201cAlcohol \u201dhttps:\/\/www.who.int\/news\u2010room\/fact\u2010sheets\/detail\/alcohol."},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejim.2022.05.016"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-021-01670-3"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881114527362"},{"key":"e_1_2_13_6_1","unstructured":"Selincro \u201cINN\u2010Nalmefene\u2014EMA \u201dhttps:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/selincro\u2010epar\u2010product\u2010information_en.pdf."},{"key":"e_1_2_13_7_1","unstructured":"Otsuka Pharmaceutical Co. L \u201cSelincro (Nalmefene) Tablets 10\u2009mg Receives Regulatory Approval in Japan\u201d(2019) https:\/\/www.otsuka.co.jp\/en\/company\/newsreleases\/2019\/20190108_1.html."},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2012.10.020"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euroneuro.2013.02.006"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X21666221229160300"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1990.03450190043026"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jad.2010.12.014"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00127-014-0855-7"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.213793"},{"key":"e_1_2_13_15_1","unstructured":"Otsuka Pharmaceutical Co. Ltd \u201cU.S. FDA Approves Otsuka and Lundbeck's REXULTI (Brexpiprazole) as Adjunctive Treatment for Adults With Major Depressive Disorder and as a Treatment for Adults With Schizophrenia 2015 \u201dhttps:\/\/www.otsuka.co.jp\/en\/company\/newsreleases\/2015\/20150713_1.html."},{"key":"e_1_2_13_16_1","unstructured":"Otsuka and Lundbeck \u201cAnnounce U.S. Food and Drug Administration (FDA) Approval of Supplemental New Drug Application (sNDA) for REXULTI (Brexpiprazole) for the Treatment of Agitation Associated With Dementia due to Alzheimer's Disease \u201d[press release] (2023)."},{"key":"e_1_2_13_17_1","unstructured":"Otsuka Pharmaceutical Co. Ltd \u201cOtsuka Obtains Additional Indication for Rexultiin Japan as an Adjunctive Treatment for Agitation Associated With Dementia due to Alzheimer's Disease 2024 \u201dhttps:\/\/www.otsuka.co.jp\/en\/company\/newsreleases\/2024\/20240924_2.html."},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/alcalc\/36.1.2"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.213819"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0741-8329(92)90045-C"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-008-1267-8"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.alcohol.2012.01.001"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/pcn.12914"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.12915"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/acer.13568"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01789-z"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2022.02.006"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0151242"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/npr2.12461"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0456-22.2023"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2021.1890275"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2021.1897898"}],"container-title":["Neuropsychopharmacology Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/npr2.70107","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/npr2.70107","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/npr2.70107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T06:51:59Z","timestamp":1779691919000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/npr2.70107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["10.1002\/npr2.70107"],"URL":"https:\/\/doi.org\/10.1002\/npr2.70107","archive":["Portico"],"relation":{},"ISSN":["2574-173X","2574-173X"],"issn-type":[{"value":"2574-173X","type":"print"},{"value":"2574-173X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3]]},"assertion":[{"value":"2025-06-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70107"}}