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Operant cocaine self-administration studies in laboratory mice offer a powerful method to dissect the biology of this progression from initiation, dose-response, extinction, and cued reinstatement in a controlled, tractable system. However, many such studies encompass limited genetic diversity and rarely examine self-administration behaviors beyond the acquisition stage. Here, we study three high-diversity mouse populations \u2013 50 strains from the Collaborative Cross (CC) reference panel, a large sample of Diversity Outbred (J: DO) population and their eight founder strains \u2013 to characterize the varied phenotypic manifestation of behaviors across multiple phases of cocaine intravenous self-administration (IVSA) in both sexes. We observed distinct strain differences among the founders and CC strains in all phases of self-administration, with heritability estimates ranging from 0 to 0.585 and many CC and J: DO phenotypic values exceeding the range of founders including the C57BL\/6J strain. Sex differences were common across behaviors, some manifesting as main effects, others as strain interactions. Finally, by adopting a multi-stage design, we identified extreme strains for various cocaine intake and response traits. Together, these findings demonstrate the utility of extended self-administration protocols in high-diversity mouse populations and establish feasibility for their use in the discovery and characterization of biological mechanisms of substance use traits and for preclinical studies in relevant, complex mouse models.<\/jats:p>","DOI":"10.1007\/s00213-025-06904-w","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T07:47:59Z","timestamp":1757922479000},"page":"1513-1528","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Behavioral variation across multiple phases of intravenous cocaine self-administration among genetically diverse mouse populations"],"prefix":"10.1007","volume":"243","author":[{"given":"Price E.","family":"Dickson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udita","family":"Datta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Troy D.","family":"Wilcox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley A.","family":"Auth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn L.","family":"Ball","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Dunn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi S.","family":"Fisher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Leonardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler A.","family":"Roy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Saul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason A.","family":"Bubier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leona H.","family":"Gagnon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek M.","family":"Philip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"Tarantino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Jentsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5642-5062","authenticated-orcid":false,"given":"Elissa J.","family":"Chesler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"issue":"3","key":"6904_CR1","doi-asserted-by":"publisher","DOI":"10.1111\/adb.13162","volume":"27","author":"JR Bagley","year":"2022","unstructured":"Bagley JR, Khan AH, Smith DJ, Jentsch JD (2022) Extreme phenotypic diversity in operant response to intravenous cocaine or saline infusion in the hybrid mouse diversity panel. 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