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

Nature Neuroscience volume 8, pages 212–219 (2005)Cite this article

Abstract

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.

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Figure 1: Time-dependent increases in cocaine seeking after withdrawal.
Figure 2: Exposure to cocaine cues after 30 d of withdrawal increases ERK phosphorylation in the central amygdala.
Figure 3: Exposure to cocaine cues after 30 d of withdrawal increases ERK phosphorylation in the central amygdala: a replication using rats chronically housed in the cocaine self-administration environment during the withdrawal period.
Figure 4: Inhibition of ERK phosphorylation in the central amygdala decreases cocaine seeking after 30 d of withdrawal.
Figure 6: Induction of ERK phosphorylation in the central amygdala by NMDA increases cocaine seeking after 1 d of withdrawal.
Figure 5: Blockade of NMDA receptors in the central amygdala decreases cocaine seeking and ERK phosphorylation after 30 d of withdrawal.
Figure 7: Inhibition of ERK activity in the central amygdala has no effect on lever responding reinforced by cocaine or palatable food.

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Acknowledgements

We thank S. Gray, D. Nagarkar, D. Chuang and C. Scheidweiler for technical assistance, and J. Stewart, D.E. Epstein, B.J. Everitt and R.A. Wise for helpful comments and critical discussions of the present data. Research was supported by the National Institute on Drug Abuse Intramural Research Program.

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  1. Department of Health and Human Services, Behavioral Neuroscience Branch, Intramural Research Program/National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, 21224, Maryland, USA

    Lin Lu, Bruce T Hope, Jack Dempsey, Shirley Y Liu, Jennifer M Bossert & Yavin Shaham

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Correspondence to Yavin Shaham.

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Lu, L., Hope, B., Dempsey, J. et al. Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci 8, 212–219 (2005). https://doi.org/10.1038/nn1383

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