Central amygdala ERK signaling pathway is critical to incubation of cocaine craving.

Using a rat model of craving and relapse, we have previously found time-dependent increases in cue-induced cocaine seeking over the first months of withdrawal from cocaine, suggesting that drug craving incubates over time. Here, we explored the role of the amygdala extracellular signal-regulated kinase (ERK) signaling pathway in this incubation. Cocaine seeking induced by exposure to cocaine cues was substantially higher after 30 withdrawal days than after 1 withdrawal day. Exposure to these cues increased ERK phosphorylation in the central, but not the basolateral, amygdala after 30 d, but not 1 d, of withdrawal. After 30 d of withdrawal from cocaine, inhibition of central, but not basolateral, amygdala ERK phosphorylation decreased cocaine seeking. After 1 d of withdrawal, stimulation of central amygdala ERK phosphorylation increased cocaine seeking. Results suggest that the incubation of cocaine craving is mediated by time-dependent increases in the responsiveness of the central amygdala ERK pathway to cocaine cues.