ESCALATION AND REINSTATEMENT OF FENTANYL SELF-ADMINISTRATION IN MALE AND FEMALE RATS

Escalation of intake and craving are two DSM-5 hallmark symptoms of opioid use disorder (OUD). Objectives: This study determined if escalation measured by long access (LgA) self-administration and craving measured by reinstatement are related. Adult male and female Sprague-Dawley rats were trained to self-administer (SA) fentanyl across 7 daily 1-h sessions, followed by 21 SA sessions of either 1- or 6-h duration. Assignment to short access (ShA) and long access (LgA) groups was randomly determined for both males and females. Following 14 1-h extinction sessions, Experiment 1 assessed reinstatement induced by either fentanyl (10 or 30 μg/kg) or yohimbine (1 or 2 mg/kg), while Experiment 2 assessed reinstatement induced by a drug-associated cue light. Females acquired fentanyl SA faster than males and self-administered more than males throughout escalation. In extinction, compared to ShA rats, LgA rats initially responded less and showed less decay of responding across sessions. A fentanyl prime induced reinstatement, with LgA rats reinstating more than ShA rats at the 30 μg/kg dose; this effect of was specific to males. Yohimbine (1 mg/kg) also induced reinstatement, but there was no effect of access group or sex. With cue-induced reinstatement, LgA females responded less than LgA males and ShA females; the reduced fentanyl seeking to a cue in LgA females may reflect a general decrease in behavior, as this group also showed suppressed locomotor activity in a different context. Among the different reinstatement tests assessed, escalation of fentanyl SA in the LgA group increased only drug-primed reinstatement and only in males, suggesting a limited relationship between escalation of intake and craving (reinstatement) for OUD