Inhibition of ERK1/2 or CRMP2 Disrupts Alcohol Memory Reconsolidation and Prevents Relapse in Rats

Nofar Rahamim, Mirit Liran, Coral Aronovici, Hila Flumin, Tamar Gordon, Nataly Urshansky, Segev Barak*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Relapse to alcohol abuse, often caused by cue-induced alcohol craving, is a major challenge in alcohol addiction treatment. Therefore, disrupting the cue-alcohol memories can suppress relapse. Upon retrieval, memories transiently destabilize before they reconsolidate in a process that requires protein synthesis. Evidence suggests that the mammalian target of rapamycin complex 1 (mTORC1), governing the translation of a subset of dendritic proteins, is crucial for memory reconsolidation. Here, we explored the involvement of two regulatory pathways of mTORC1, phosphoinositide 3-kinase (PI3K)-AKT and extracellular regulated kinase 1/2 (ERK1/2), in the reconsolidation process in a rat (Wistar) model of alcohol self-administration. We found that retrieval of alcohol memories using an odor-taste cue increased ERK1/2 activation in the amygdala, while the PI3K-AKT pathway remained unaffected. Importantly, ERK1/2 inhibition after alcohol memory retrieval impaired alcohol-memory reconsolidation and led to long-lasting relapse suppression. Attenuation of relapse was also induced by post-retrieval administration of lacosamide, an inhibitor of collapsin response mediator protein-2 (CRMP2)—a translational product of mTORC1. Together, our findings indicate the crucial role of ERK1/2 and CRMP2 in the reconsolidation of alcohol memories, with their inhibition as potential treatment targets for relapse prevention.

Original languageEnglish
Article number5478
JournalInternational Journal of Molecular Sciences
Volume25
Issue number10
DOIs
StatePublished - May 2024

Funding

FundersFunder number
Tel Aviv University
United States-Israel Binational Science Foundation2017022
United States-Israel Binational Science Foundation
Israel Science Foundation508/20
Israel Science Foundation

    Keywords

    • CRMP2
    • ERK1/2
    • addiction
    • alcohol
    • memory reconsolidation
    • signaling

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