Reinforcing and psychostimulant effects of carfentanil and morphine in mice

Carfentanil is a widely used opioid new psychoactive substance (NPS) that possesses a high risk of addiction. However, the positive and negative reinforcement, as well as the psychostimulant effects of carfentanil remain unclear. In the present study, we compared the rewarding (positive reinforcement) and psychostimulant effects between carfentanil and morphine, using the conditioned place preference (CPP, including acquisition, extinction, and reinstatement) and behavioral sensitization paradigms. The withdrawal syndrome and anxiety- and depressive-like behaviors were detected to reveal the drug withdrawal-induced somatic and psychiatric symptoms (associated with negative reinforcement). Our results demonstrated that a low dose (0.5 μg/kg) of carfentanil could induce comparable CPP acquisition to 10 mg/kg morphine. Carfentanil, but not morphine, successfully induced behavioral sensitization. Both carfentanil and morphine withdrawal led to somatic and psychiatric (anxiety- and depressive- like behaviors) symptoms. Notably, carfentanil-exposed mice demonstrated more severe somatic withdrawal symptoms compared to morphine-exposed mice after naloxone-precipitation. In the drug-induced acquisition of CPP, carfentanil-exposed mice, but not morphine-exposed mice, showed an increase of c-Fos expression in the shell of nucleus accumbens (NAcSh) and caudate putamen (CPu). In the naloxone-precipitated drug withdrawal, carfentanil-exposed mice exhibited a higher level of c-Fos expression than morphine-exposed mice in the CPu. Carfentanil, but not morphine, activated the prefrontal cortex (PFC), NAcSh, and dorsal hippocampus (dHPC). Collectively, we found more potent reinforcing and psychostimulant effects of carfentanil compared to morphine. Our findings extend the knowledge and lay the foundation for the mechanistic studies of the reinforcing and psychostimulant effects of NPSs.