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We examined whether common genetic variation in outbred Sprague\u2013Dawley rats explained variation in behavioral measures from three assays with established links to substance use: locomotor response to a novel environment, elevated plus maze, and tail flick. We estimated single\u2010nucleotide polymorphism heritability and performed genome\u2010wide association analyses using permutation\u2010derived significance thresholds (\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u2009534\u2013654 rats across traits). Heritability estimates ranged from 0.14 to 0.38 across 11 traits. Three independent loci were identified: chromosome 1 for elevated plus maze open\u2010arm behavior (\n                    <jats:italic>\u03b1<\/jats:italic>\n                    \u2009=\u20090.05), chromosome 14 for elevated plus maze immobility (\n                    <jats:italic>\u03b1<\/jats:italic>\n                    \u2009=\u20090.10), and chromosome 17 for tail flick latency (\n                    <jats:italic>\u03b1<\/jats:italic>\n                    \u2009=\u20090.05). Candidate genes included\n                    <jats:italic>Slc18a2<\/jats:italic>\n                    ,\n                    <jats:italic>Gfra1<\/jats:italic>\n                    , and\n                    <jats:italic>Pdzd8<\/jats:italic>\n                    (chromosome 1);\n                    <jats:italic>Rel<\/jats:italic>\n                    and\n                    <jats:italic>Bcl11a<\/jats:italic>\n                    (chromosome 14); and\n                    <jats:italic>Eci2<\/jats:italic>\n                    and\n                    <jats:italic>Eci3<\/jats:italic>\n                    (chromosome 17). We compared these loci with our genome\u2010wide association study of a F\n                    <jats:sub>2<\/jats:sub>\n                    intercross of selectively bred high\u2010 and low\u2010responder rats, originally derived from Sprague\u2013Dawleys, that model individual differences in externalizing and internalizing behavior. The current loci are distinct from the ones identified in the bred lines. This difference likely reflects selection history in the high\u2010 and low\u2010responder F\n                    <jats:sub>2<\/jats:sub>\n                    s, which focused on facets of exploratory locomotion, while loci for anxiety and pain sensitivity traits were identified in the outbreds. This highlights the benefit of using both outbred and selectively bred rats to probe causal variants contributing to individual differences in substance use liability. The current outbred findings implicate monoaminergic signaling, transcriptional control, and lipid metabolism as testable mechanisms for addiction\u2010relevant behaviors.\n                  <\/jats:p>","DOI":"10.1111\/gbb.70053","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T09:32:15Z","timestamp":1779096735000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Architecture of Addiction\u2010Relevant Behaviors in Outbred Sprague\u2013Dawley Rats Reveals Loci for Anxiety\u2010Like and Nociceptive Traits"],"prefix":"10.1111","volume":"25","author":[{"given":"Apurva S.","family":"Chitre","sequence":"first","affiliation":[{"name":"Department of Psychiatry University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine K.","family":"Hebda\u2010Bauer","sequence":"additional","affiliation":[{"name":"Michigan Neuroscience Institute University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Emery","sequence":"additional","affiliation":[{"name":"Michigan Neuroscience Institute University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Li","sequence":"additional","affiliation":[{"name":"Michigan Neuroscience Institute University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khai\u2010Minh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of California San Diego  La Jolla California 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Center, College of Medicine  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huda","family":"Akil","sequence":"additional","affiliation":[{"name":"Michigan Neuroscience Institute University of Michigan  Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3634-0747","authenticated-orcid":false,"given":"Abraham A.","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Psychiatry University of California San Diego  La Jolla California USA"},{"name":"Institute for Genomic Medicine University of California San Diego  La Jolla California 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