A morphine reward generalization mouse model based on conditioned place preference and aversion

Background: Conditioned place preference (CPP) is a common behavioral paradigm for studying the association of unconditioned stimulus reward memory with context. Generalization is a flexible memory recall pattern developed on the basis of original memory. Drug-seeking behaviors in substance use disorders (SUDs) exhibit diversity, which we generally attribute to the highly generalized features of SUD memory. However, to date, there are no animal models for SUD generalization studies.

Methods: We design the generalization box (G-box) and the generalization retrieval process based on the conditioned place preference (CPP) model. In the memory retrieval stage, we replaced the conditioning CPP box (T-box) with a generalization box (G-box) to study drug generalization memory. For appearance, the generalized boxes have different angles and numbers of sides compared to the conditioning boxes. For the visual cues, the shapes of the symbols are different (triangle icons for the hexagonal chamber and dot icons for the round chamber), but the orientation information remains the same. To establish CPP generalization, the mice received morphine on the vertical or horizontal side of a conditioning box (T-box) and saline on the other side. Then, after CPP conditioning, the generalization test was performed in a generalization box (G-box: hexagonal chamber and Gr-box: round chamber) 21 days later.

Results: CPP-conditioned mice still displayed a clear preference for similar visual information in the G-box. CPA-conditioned mice behaved similarly to CPP, with mice consistently avoiding similar visual information in the G-box. We further observed that the generalization results are similar using two generalization boxes (G-box and Gr-box).

Conclusion: In this study, we succeeded in creating a simple and effective generalization model for morphine reward. The establishment of this model provides a new tool for generalization studies of SUD and therapy in humans.