Retrieval of morphine‐associated context induces cFos in dentate gyrus neurons

Addiction has been proposed to emerge from associations between the drug and the reward-associated contexts. This associative learning has a cellular correlate, as there are more cFos+ neurons in the hippocampal dentate gyrus (DG) after psychostimulant conditioned place preference (CPP) vs. saline controls. However, it is unknown whether morphine CPP leads to a similar DG activation, or whether DG activation is due to locomotion, handling, pharmacological effects, or – as data from contextual fear learning suggests – exposure to the drug-associated context. To explore this, we employed an unbiased, counterbalanced, and shortened CPP design that led to place preference, more DG cFos+ cells, and yet decreased locomotion. Next, mice underwent morphine CPP but were then sequestered into the morphine-paired (conditioned stimulus+ [CS+]) or saline-paired (CS−) context on test day. Morphine-paired mice sequestered to CS+ had ~30% more DG cFos+ cells than saline-paired mice. Furthermore, Bregma analysis revealed morphine-paired mice had more cFos+ cells in CS+ compared to CS− controls. Notably, there was no significant difference in DG cFos+ cell number after handling alone or after receiving morphine in home cage. Thus, retrieval of morphine-associated context is accompanied by activation of hippocampal DG granule cell neurons.