Effects of the Veterinary Anesthetic Xylazine on the Discriminative Stimulus Effects of the Opioid Agonist Fentanyl in Rats

Abstract ID 94514 Poster Board 107 Fentanyl adulterated with the alpha2-adrenoreceptor agonist xylazine is becoming increasingly more common and further escalating the opioid crisis in many major cities. Some people who inject drugs report xylazine extends the effects of fentanyl which are short acting. Little is known about the pharmacological interactions of fentanyl and xylazine in preclinical models of abuse liability. To test the notion that xylazine will substitute for or prolong the subjective effects of the mu opioid agonist fentanyl, 12 Sprague-Dawley rats were trained to discriminate between saline and a dose of 0.01 mg/kg fentanyl in a two-choice drug discrimination procedure using an FR10 schedule of sucrose pellet delivery. During training, rats were injected subcutaneously with saline or fentanyl and placed in the experimental chamber. After a pretreatment of 10 minutes, rats had 15 min to earn a maximum of 50 pellets. Rats met testing criteria after an average of 10 training sessions at FR10. Fentanyl (0.001-0.02 mg/kg) produced dose-dependent increases in fentanyl lever responding and decreases in response rats. A dose of 1.0 mg/kg xylazine produced approximately 25% fentanyl lever responding with significant rate-decreasing effects. A time-course for the training dose of 0.01 mg/kg fentanyl was established. After a 20 min pretreatment, only 40% fentanyl lever responding was recorded and after a 30 min pretreatment, most rats responded on the saline lever. Co-administration of increasing doses of xylazine significantly augmented the fentanyl lever responding after 30 min compared to 0.01 mg/kg fentanyl alone. These data demonstrate that while xylazine does not substitute for the discriminative stimulus effects of fentanyl, xylazine can prolong the time course of fentanyl in rats. Supported by Pilot Project Core from NIH 5P30DA013429 to EAW, BRIDGE R25NS130632 to MLN, EAW.