The Activation of NMDA Receptor-ERK Pathway in the Central Amygdala is Required for the Expression of Morphine-Conditioned Place Preference in the Rat

Reinforcing effects of addictive drugs can be evaluated with the conditioned place preference (CPP) test which involves both the action of drugs and environmental cues. However, the encoded neural circuits and underlying signaling mechanism are not fully understood. In this study, we have used morphine-CPP model in the rat and characterized the role of N-methyl-D-aspartate (NMDA) receptor and the phosphorylation of extracellular signal-regulated kinase (ERK) in the central nuclei of amygdala (CeA) in the expression of morphine-induced CPP. We have found that morphine repeated pairing treatment causes a significant preference for compartment paired with morphine after 1 day or 7 days post-training, which is associated with increased ERK1/2 phosphorylation (p-ERK1/2, a measure of ERK activity) in the CeA. More than 80% of the positive p-ERK1/2 neurons express NMDA receptor subunit NR1 by double immunofluorescence studies. The infusion of either MEK inhibitor U0126 or NMDA receptor antagonist MK-801 in the CeA not only suppresses the activation of ERK1/2 in the CeA but also abolishes the expression of CPP. These results suggest that the activation of the NMDA receptor-ERK signaling pathway in the CeA is required for the expression of morphine-induced place preference in the rat.