Escalation and reinstatement of fentanyl self-administration in male and female rats

Rationale: Escalation of drug intake and craving are two DSM-5 hallmark symptoms of opioid use disorder (OUD). Objectives: This study determined if escalation of intake as modeled by long access (LgA) self-administration (SA) and craving measured by reinstatement are related. Methods: Adult male and female Sprague–Dawley rats were trained to self-administer fentanyl across 7 daily 1-h short access (ShA) sessions, followed by 21 SA sessions of either 1- or 6-h duration (ShA or LgA). 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), and Experiment 2 assessed reinstatement induced by a drug-associated cue light. Results: Females acquired fentanyl SA faster than males. When shifted to LgA sessions, LgA rats escalated fentanyl intake, but ShA rats did not; no reliable sex difference in the rate of escalation was observed. In extinction, compared to ShA rats, LgA rats initially responded less and showed less decay of responding across sessions. A priming injection of fentanyl induced reinstatement, with LgA rats reinstating more than ShA rats at the 30 µg/kg dose. Yohimbine (1 mg/kg) also induced reinstatement, but there was no effect of access group or sex. With cue-induced reinstatement, LgA females reinstated less than LgA males and ShA females. Conclusion: Among the different reinstatement tests assessed, escalation of fentanyl SA increased only drug-primed reinstatement, suggesting a limited relationship between escalation of drug intake and craving (reinstatement) for OUD.