Abstract
<jats:p>Pre-clinical models of opioid use disorder are essential for characterizing the neural mechanisms that drive persistent opioid seeking and relapse and, ultimately, revealing new targets for therapeutic intervention. Here, we establish a surgery-free oral fentanyl self-administration procedure in male and female C57BL/6 and CD1 mice that measures intake, escalation, maintenance, extinction, and cued-reinstatement. Our model combines voluntary seeking with oral intake, providing an alternative to intravenous or vapor self-administration models. We demonstrate a 75% acquisition rate across all mice for fentanyl self-administration, with increased responding as fentanyl concentration decreased, indicating regulation of intake. C57BL/6 mice escalated their intake across self-administration sessions, showed increased seeking during early extinction followed by a marked decrease, and reinstated seeking following presentation of a conditioned audio-visual cue. CD1 mice showed an immediate high intake and sensitivity of reward-port approach tendencies to an audio-visual cue. Sex differences were limited and originated largely in C57BL/6 mice. Fentanyl use risk severity scores varied within both strains, conveying distinct behavioral profiles for severity within each strain.</jats:p>