Further characterization of oral fentanyl self-administration in male and female Sprague Dawley rats.

Fentanyl is a potent synthetic opioid with high misuse potential and risk for overdose. While primarily associated with the intravenous route of administration, fentanyl is now often found in pills. However, few preclinical studies have assessed oral self-administration of fentanyl. In the present study, different groups of male and female Sprague Dawley rats were tested in a series of paradigms to further characterize oral fentanyl self-administration. Rats were trained to self-administer various doses of fentanyl (2.0-50.0 μg/ml) in the presence or the absence of a drug-paired stimulus and were trained to self-administer fentanyl (2.0 or 25.0 μg/ml) across increasing response requirements. Rats were also assessed for cue- and drug-induced reinstatement of fentanyl seeking, as well as for incubation of fentanyl seeking in the absence of discrete drug-paired stimuli and for resurgence of fentanyl seeking. With one exception, females responded more for fentanyl relative to males. As expected, the presence of a drug-paired stimulus significantly enhanced fentanyl self-administration and reinstated drug seeking. Consistent with previous work, we found that incubation of fentanyl seeking does not occur when a proximal cue is omitted during self-administration training. Oral fentanyl self-administration did not produce the standard U-shaped dose-response function; furthermore, rats showed little motivation to earn fentanyl across increasing response requirements. Drug-induced reinstatement was not observed when rats were trained with a low concentration of fentanyl (2.0 μg/ml). Resurgence of fentanyl (50.0 μg/ml) seeking was also not observed. Overall, additional work is needed to fully characterize addictive-like behaviors using oral fentanyl self-administration paradigms.