Xylazine co-administration influences the rewarding properties of heroin and withdrawal in male rats

The current opioid use disorder crisis has been further complicated by the adulteration of the drug supply with the veterinary sedative xylazine. Xylazine is not approved for human use and is associated with numerous adverse effects when consumed. While most existing research has examined the consequences of fentanyl-xylazine co-administration, to date, no studies have explored the behavioral and withdrawal effects of heroin-xylazine co-administration. In the current study, we used a contingent model of heroin-xylazine (0.02 and 0.15 mg/kg/infusion) co-administration to demonstrate that in male rats, heroin consumption and motivation are attenuated when xylazine is co-administered with heroin. However, co-administration with xylazine potentiated cue-induced drug-seeking behavior following 10 days of extinction. In a separate cohort, we evaluated the impact of our selected xylazine dose on locomotion and found that it did not induce sedation, implicating that the behavioral effects produced were not confounded by locomotor suppression. We also assessed naloxone-precipitated withdrawal (1 mg/kg, s.c) and observed a reduction in total somatic withdrawal signs in the heroin-xylazine group, an effect not seen in the heroin-only group. Surprisingly, these reduced somatic signs did not extend to all behavioral modalities and diverged based on the type of somatic signs. These findings suggest that xylazine may function as a satiety-enhancing agent when co-administered with heroin, as evidenced by the suppression of self-administration. However, xylazine's effect on precipitating cue-induced reinstatement reveals the synergistic potential of its adulteration during relapse.