Reinforcing Effects of Fentanyl and a Fentanyl Analog Found in Illicit Drug Markets

HYPOTHESIS Illicitly manufactured fentanyl and fentanyl analogs are the main drivers of the worsening opioid epidemic. Although the pharmacology of fentanyl is well characterized, there is little information about the reinforcing effects of newly emerging fentanyl analogs that are contributing to opioid overdose. Here, we compare the effects of fentanyl and the clandestine fentanyl analog, cyclopropylfentanyl, on drug self‐administration behavior in male and female rats. METHODS Sprague‐Dawley rats fitted with intravenous (i.v.) jugular catheters were placed in experimental chambers containing two nose poke holes. Active nose poke responses resulted in delivery of a constant volume of drug (0.2 mL) over a period of 2 s on a fixed‐ratio 1 schedule, followed by a 20 s timeout. Acquisition doses for the compounds were 0.01 mg/kg/inj for fentanyl and cyclopropylfentanyl, while 0.1 mg/kg/inj was used for heroin. Following 10 days of acquisition training, dose‐effect testing began with three additional doses, each of which were tested for 3 days. Subjects then returned to the original training dose until responses stabilized and underwent saline extinction. RESULTS Acquisition of fentanyl self‐administration was achieved by both male and female rats, with significant differences between active versus inactive nose pokes for both sexes over the last 4 days of training (p<0.05). A similar profile of acquisition was seen for heroin and cyclopropylfentanyl. Both fentanyl and cyclopropylfentanyl showed a typical inverted‐U dose‐effect function during dose‐effect testing. Maximal response rates were similar among all drugs, with fentanyl showing maximum responding at 0.001 mg/kg/inj, cyclopropylfentanyl at 0.003 mg/kg/inj, and heroin at 0.003 mg/kg/inj. CONCLUSION Both male and female rats showed comparable rates of fentanyl acquisition. Further comparison between heroin, fentanyl, and cyclopropylfentanyl show that these compounds support self‐administration, indicating that emerging fentanyl analogs display significant abuse liability and may contribute to compulsive use in humans.