Key determinants for morphine withdrawal conditioned context-induced increase in Arc expression in anterior cingulate cortex and withdrawal memory retrieval

Addiction memory is subjected to time-dependent shifts toward neocortex in remote period to promote long-term addiction memory storage, which plays an important role in drug relapse. However, how the activity and neuroplasticity of the anterior cingulate cortex (ACC) change after contextual morphine withdrawal conditioning and what factors determine this change remain to be determined. In this paper, using immunohistochemical and single-cell microinjection techniques, combining behavioral assay, we found that (1) contextual withdrawal conditioning increases the expression of c-Fos, but not Arc, in the ACC in morphine withdrawal mice; (2) at the first day after conditioning, conditioned context has no influence on the expression of c-Fos and Arc in the ACC in morphine withdrawal mice; (3) at the 14th day after conditioning, conditioned context increases the expression of both c-Fos and Arc in the ACC in morphine withdrawal mice; (4) the inhibition of dendritic spines of the ACC or projection neurons from the CA3 of the hippocampus to the ACC attenuates the conditioned context-induced increase of Arc expression in the ACC and abolishes the retrieval of withdrawal memory at the 14th day after conditioning. These results suggest that the ACC may exhibit a change in neuroplasticity at the 14th day after conditioning, and the dendritic spines of the ACC and the projection neurons from the CA3 of the hippocampus to the ACC are key determinants for conditioned context induced-increase in Arc expression in the ACC and the retrieval of withdrawal memory at the 14th day after conditioning.