Changes in the levels of p-ERK, p-CREB, and c-fos in rat mesocorticolimbic dopaminergic system after morphine-induced conditioned place preference: the role of acute and subchronic stress.

ERK pathway plays a critical role in the cellular adaptive responses to environmental changes. Stressful conditions can induce the activation of activate ERK, and its downstream targets, CREB and c-fos, in neural cells. Exposure to opioids has the same effect. In this study, we investigated the effects of morphine-induced conditioned place preference (CPP) on p-ERK/ERK ratio, p-CREB/CREB ratio and c-fos level in the mesocorticolimbic dopaminergic system including the nucleus accumbens (NAc), amygdala (AMY), striatum (Str), and prefrontal cortex (PFC).Our aim was to determine if acute and subchronic stress would affect these alterations. Male Wistar rats were divided into two saline- and morphine-treated groups. Each group contained of control, acute stress, and subchronic stress subgroups. The CPP procedure was performed for all of the rats. We dissected out the NAc, AMY, Str, and PFC regions and measured the mentioned ratios and c-fos level by Western blot analysis. The results revealed that in saline-treated animals, all factors enhanced significantly after performing acute and subchronic stress while there was an exception in p-ERK/ERK ratio in the Str and PFC; the changes were not significant during acute stress. Conditioning score decreased after applying the subchronic but not acute stress. In morphine-treated animals, all factors were increased after application of acute and subchronic stress, and conditioning scores also decreased after stress. Our findings suggest that in saline- or morphine-treated animals, acute and subchronic stress increases p-ERK, p-CREB, and c-fos levels in the mesocorticolimbic system. It has been shown that morphine induces the enhancement of the mentioned factors; on the other hand, our result demonstrates that stress can amplify these changes.