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While <jats:italic>Drosophila<\/jats:italic> has been critical for identifying novel molecular and neural circuit mechanisms underlying alcohol responses, few studies assess the use of <jats:italic>Drosophila<\/jats:italic> for the investigation and discovery of pharmacological targets of alcohol use disorder (AUD). Determining appropriate doses that impact alcohol consumption and memory for alcohol reward without affecting acute locomotor responses is key to identifying effective AUD medications such as naltrexone, acamprosate, and topiramate. This pipeline can then be used to test novel pharmacotherapies, including \u03b3\u2010secretase inhibitors (such as dibenzazepine and compound E) as potential treatments for AUD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To validate <jats:italic>Drosophila<\/jats:italic> as an effective model for studying pharmacological therapies for AUD, we identified nondisruptive drug doses in flies using feeding and locomotive assays. Then, we assessed their impact on ethanol consumption and conditioned preference in cue\u2010induced alcohol\u2010seeking after 1 or 3\u2009days of training.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Naltrexone and acamprosate significantly reduced ethanol food preference and 3\u2010day conditioned preference, while topiramate did not. \u03b3\u2010secretase inhibitors dibenzazepine and compound E significantly decreased conditioned preference after 3\u2009days.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>Drosophila<\/jats:italic> is a valuable model organism for identifying and characterizing new AUD pharmacotherapies.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.70146","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T15:00:08Z","timestamp":1759158008000},"page":"2294-2309","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Investigating pharmacotherapies for alcohol use disorder using <i>Drosophila melanogaster<\/i>"],"prefix":"10.1111","volume":"49","author":[{"given":"Rebecca","family":"Oramas","sequence":"first","affiliation":[{"name":"Department of Neuroscience Brown University  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanabah","family":"Jaques","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Brown University  Providence Rhode Island USA"},{"name":"Department of Neuroscience University of California Berkeley  Berkeley California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie M.","family":"D'Silva","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Brown University  Providence Rhode Island USA"},{"name":"Career and Postdoctoral Development Office The Scripps Research Institute  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Azanchi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Brown University  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John E.","family":"McGeary","sequence":"additional","affiliation":[{"name":"Providence VA Medical Center  Providence Rhode Island USA"},{"name":"Department of Psychiatry &amp; Human Behavior Brown University  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8756-9528","authenticated-orcid":false,"given":"Karla R.","family":"Kaun","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Brown University  Providence Rhode Island USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107454"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2013.03.004"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300657"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u20100716\u20102970\u20103_13"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530\u20100277.1998.tb03636.x"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014\u20102999(99)00245\u20109"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3791\/61181"},{"key":"e_1_2_9_9_1","volume-title":"Incorporating alcohol pharmacotherapies into medical practice","author":"Center for Substance Abuse Treatment","year":"2009"},{"key":"e_1_2_9_10_1","unstructured":"Centers for Disease Control and Prevention. 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