Rewarding and reinforcing effects of the NMDA receptor antagonist–benzodiazepine combination, zoletil®: Difference between acute and repeated exposure

► Tiletamine is rewarding and reinforcing in rats. ► Zolazepam induced place preference but not self-administration. ► Acute zoletil treatment produced neither reward nor reinforcement. ► Repeated zoletil treatment produced place preference and self-administration. Zoletil® is a 1:1 combination of the N-methyl-d-aspartate (NMDA) receptor antagonist, tiletamine, and the benzodiazepine, zolazepam, commonly used as a veterinary anesthetic. There have been previous reports on the abuse of zoletil in humans, and these motivated us to investigate the rewarding and reinforcing effects of the drug. We experimented whether zoletil and its constituents, tiletamine and zolazepam, produces place preference and/or facilitates self-administration. Then we compared the effects of zoletil to that of the recreationally abused veterinary anesthetic, ketamine. We also delved into the consequences of drug pre-exposure, thus parallel experiments were performed on rats pre-treated with the drug for 14 days. Our findings indicated that zoletil produced neither reward nor reinforcement in drug-naïve rats; however, repeated pre-treatment of zoletil produced significant place preference and self-administration. Tiletamine generated both place preference and self-administration; while zolazepam induced place preference but was not self-administered, even in pre-treated animals. The rewarding and reinforcing effects produced by zoletil were comparable to that of ketamine. Therefore, zoletil per se, has no motivational effects but the changes in neuronal functions and behavior consequential to repeated zoletil treatment may contribute in part to the addiction liability of the drug. Furthermore, the present study suggests that complex interactions occur with acute or repeated treatment of an NMDA receptor antagonist-benzodiazepine combination.