A mouse model of oxycodone reward following its oral self-administration in a sweetened solution

This study aimed to develop a preclinical model in which reinforcement and reward can be measured in the same subject. To this end, we combined the power of drug self-administration and place conditioning paradigms and determined whether voluntary oral oxycodone self-administration would induce conditioned place preference (CPP) and whether this response could be extinguished and reinstated. To assess the face validity of the model, we also evaluated the role of the mu-opioid receptor (MOP) in this process.

Male and female C57BL/6 mice, as well as male MOP knockout mice and their wild-type littermates, were initially conditioned with sucrose (4%) in both conditioning chambers for 1 h daily for 2 weeks (4 days a week). Mice were then tested for basal place preference and then underwent alternate-day conditioning (1 h daily) with sucrose (4%) in one chamber and oxycodone in a 4% sucrose solution in the opposite chamber the following day for four consecutive days, followed by a CPP test. The following week, another set of conditioning and testing for CPP was repeated. Subsequently, mice were exposed to the sucrose (45) solution alone for 4 days each week, and a test for extinction of the CPP response at the end of each week. After extinction, mice were challenged with oxycodone (5 mg/kg) and tested for the reinstatement of CPP.

Both male and female mice demonstrated robust voluntary oral oxycodone self-administration in a 4% sucrose solution, but it was lower in females than in males. Oxycodone self-administration was associated with CPP in male and female mice. This response was extinguished and reinstated. Unlike wild-type mice, the CPP response was not observed in mice lacking MOP, suggesting that MOP is involved in this response.

This is the first study providing evidence for the development of a translational mouse model of reward utilizing oral oxycodone self-administration in a sweetened solution.