Effects of fentanyl and the adulterant levamisole on the rewarding and locomotor effects of methamphetamine in rats

People who use psychostimulant substances can be exposed to unknown adulterants, such as the synthetic opioid fentanyl (FEN) and the anthelmintic cholinergic agent levamisole (LEV). This work explores the rewarding and locomotor effects of methamphetamine (METH) in combination with FEN or LEV. We used adult male Wistar rats in the conditioned-place preference (CPP) paradigm (conditioning, extinction, and reinstatement phases) and in the open field test to study effective doses of METH, FEN, or LEV, or ineffective doses of METH+FEN or METH+LEV in combination. METH and LEV, at 1 mg/kg METH each, and 30 µg/kg FEN produced CPP. Extinction to METH- or LEV-induced CPP occurred after eight saline injections, but it took 8–26 sessions to extinguish FEN-induced CPP. A challenge dose of 0.5 mg/kg METH reinstated CPP. The same occurred with 15 µg/kg FEN but not with 0.5 or 1 mg/kg LEV. Training animals with ineffective doses of METH (0.01 mg/kg) combined with either FEN (0.3 µg/kg) or LEV (0.01 mg/kg) produced CPP. Sub-effective doses of METH or FEN alone did not induce reinstatement after extinction. However, animals challenged with LEV, METH+FEN, or METH+LEV mixtures did it. Combining FEN (3 µg/kg) with 0.1 mg/kg METH increased locomotor activity. Ineffective FEN and LEV doses mixed with METH produce effects larger than would be expected based on the effects of either drug alone. This outcome suggests a supra-additive interaction, which could increase the risk of developing a METH use disorder.