Greater persistence of responding for fentanyl in female versus male rats

Fentanyl (FEN) is a potent synthetic opioid that significantly contributes rates of opioid use disorder (OUD) and opioid-related overdoses and deaths. Sex differences in responses to morphine and other opioids exist but less is known about FEN. This study examined potential sex differences in FEN operant self-administration. To ensure that potential sex differences in self-administration were not due to motoric effects, we also tested for sex differences in FEN's effects on locomotor activity and rate-disrupting effects in schedule-controlled responding. Separate sets of male and female Sprague-Dawley rats were tested for: 1) oral FEN self-administration under an FR3 schedule under maintenance (0.025 mg/mL/delivery), extinction, and drug-induced reinstatement conditions (0.01, 0.03 mg/kg; SC); 2) schedule-controlled responding under a fixed-ratio 15 (FR15) schedule of food pellet delivery after FEN administration (0.003-0.1 mg/kg; SC); and 3) locomotor activity in an open field (0.03 mg/kg; SC). We assessed behaviors that led to drug delivery (e.g., active lever presses) as well as ineffective active and inactive lever presses. Results revealed that female rats responded at higher rates and with greater persistence versus males as evidenced by higher levels of ineffective active lever presses, greater length of time to extinguish, and heightened rates of reinstated responding across all stages of self-administration (maintenance, extinction, and reinstatement). While there were no sex differences in FEN's rate-disrupting effects, FEN led to greater locomotor activation in females compared to males. Thus, the greater persistence in FEN self-administration behaviors in females likely does not reflect sex differences in FEN-induced motoric effects.