{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:06:53Z","timestamp":1786118813484,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,4]]},"group-title":"Neuroscience","reference-count":27,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Fentanyl-related overdose deaths now commonly involve non-injection routes, yet preclinical opioid self-administration is modeled predominantly intravenously. Here we establish an oral fentanyl self-administration procedure in male and female inbred C57BL\/6 and outbred CD1 mice that measures volitional intake, cue-driven seeking, extinction, and relapse. Mice self-administered oral fentanyl (70 \u00b5g\/mL) on a fixed-ratio 1 schedule across fifteen 3-hour sessions, followed by ten extinction sessions and a cued reinstatement test. A separate cohort underwent between-session dose thresholding across a quarter-log series from 222 to 22 \u00b5g\/mL. Seventy-five percent of mice acquired self-administration, with similar rates across genetic background and sex. Responding increased as fentanyl concentration fell, indicating dose-sensitivity toward a preferred drug level. C57BL\/6 mice escalated intake and lever pressing across sessions, responded persistently early in extinction before declining, and reinstated pressing to a conditioned cue. CD1 mice consumed high levels from the outset with limited escalation and showed neither extinction nor cued reinstatement of pressing, but shortened their reward-port approach latency when cues returned. This shows that lever presses alone would have misclassified them as weakly conditioned. A composite severity score summing seven components of fentanyl-use risk varied continuously rather than splitting into high and low groups, even among inbred mice. Sex differences were largely confined to C57BL\/6 mice, in which females showed stronger cue association and higher severity scores than males. These results reveal separable escalation-prone and relapse-prone phenotypes that track genetic background. Protocols, hardware specifications, and analysis code are openly available, lowering the barrier to adopting oral fentanyl self-administration.<\/jats:p>","DOI":"10.64898\/2026.07.30.741697","type":"posted-content","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T12:01:29Z","timestamp":1785844889000},"source":"Crossref","is-referenced-by-count":0,"title":["An oral fentanyl self-administration model reveals dissociable escalation and relapse phenotypes in outbred vs inbred mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3654-271X","authenticated-orcid":false,"given":"Todd R.","family":"Appleby","sequence":"first","affiliation":[{"name":"Center for Excellence in Neurobiology of Addiction Pain and Emotion, University of Washington School of Medicine, Seattle, WA, U.S.A"},{"name":"Department of Neurobiology & Biophysics, University of Washington School of Medicine, Seattle, WA, 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas K.","family":"MacMillen","sequence":"additional","affiliation":[{"name":"Department of Neurobiology & Biophysics, University of Washington School of Medicine, Seattle, WA, 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Department of Neurobiology & Biophysics, University of Washington School of Medicine, Seattle, WA, 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sierra","family":"Schleufer","sequence":"additional","affiliation":[{"name":"Center for Excellence in Neurobiology of Addiction Pain and Emotion, University of Washington School of Medicine, Seattle, WA, U.S.A"},{"name":"Mental Illness Research, Education and Clinical Center, Puget Sound VA Health Care System, 1660 S Columbian Way, Seattle, WA 98108"},{"name":"Department of Psychiatry & Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1763-7118","authenticated-orcid":false,"given":"John F.","family":"Neumaier","sequence":"additional","affiliation":[{"name":"Center for Excellence in Neurobiology of Addiction Pain and Emotion, University of Washington School of Medicine, Seattle, WA, U.S.A"},{"name":"Mental Illness Research, Education and Clinical Center, Puget Sound VA Health Care System, 1660 S Columbian Way, Seattle, WA 98108"},{"name":"Department of Psychiatry & Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, 98105, USA"},{"name":"Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam A.","family":"Golden","sequence":"additional","affiliation":[{"name":"Center for Excellence in Neurobiology of Addiction Pain and Emotion, University of Washington School of Medicine, Seattle, WA, U.S.A"},{"name":"Department of Neurobiology & Biophysics, University of Washington School of Medicine, Seattle, WA, 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin R.","family":"Coffey","sequence":"additional","affiliation":[{"name":"Center for Excellence in Neurobiology of Addiction Pain and Emotion, University of Washington School of Medicine, Seattle, WA, U.S.A"},{"name":"Mental Illness Research, Education and Clinical Center, Puget Sound VA Health Care System, 1660 S Columbian Way, Seattle, WA 98108"},{"name":"Department of Psychiatry & Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, 98105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080609501903000_2026.07.30.741697v1.1","doi-asserted-by":"publisher","DOI":"10.15620\/cdc\/20250305008"},{"key":"2026080609501903000_2026.07.30.741697v1.2","doi-asserted-by":"crossref","unstructured":"Hochstatter, K. 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