Ketamine blocks the correlation between morphine-induced conditioned place preference and anxiety-like behaviors in mice

Patients suffering from opioid use disorder often relapse during periods of abstinence, which is posited to be caused by negative reinforcement driving motivated behaviors. Here, we explored whether opioid-seeking behaviors in mice were correlated with the negative affect of anxiety. To do this, we conditioned mice to associate a specific context with morphine, an opioid with strongly addictive properties, using a three compartment chamber. 24 h following five days of morphine (10 mg/kg, i.p.) conditioning, anxiety levels were tested by measuring time in the open arms of an elevated plus maze. The next day, mice were placed in the three compartment chamber to measure morphine-induced conditioned place preference (CPP). Our results show that following morphine conditioning, mice spent significantly less time in the open arm of the elevated plus maze, which was negatively correlated with the CPP score. Furthermore, we found that an acute treatment with ( R,S )-ketamine (10 mg/kg, i.p.), a medication demonstrating promise for preventing anxiety-related phenotypes, 30 min. prior to testing on post conditioning day 1, increased time spent in the open arm of the elevated plus maze in morphine conditioned mice. Lastly, we found that a second injection of ketamine 30 min. prior to CPP tests on post conditioning day 2 attenuated morphine-induced CPP, which lasted for up to 28 d. Overall, our results suggest that morphine-induced CPP may be driven by negative reinforcement, which can be prevented by acute ketamine administration.