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bioRxiv · 10.1101/2023.12.12.571297

ERK1/2 inhibition disrupts alcohol memory reconsolidation and prevents relapse

Rahamim, N.·Liran, M.·Aronovici, C.·Flumin, H.·Gordon, T.·Urshansky, N.·Barak, S.
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Abstract

Relapse to alcohol abuse after periods of abstinence, often caused by cue-induced alcohol craving, is a major challenge in the treatment of alcohol addiction. Therefore, disruption of the cue-alcohol associative memories can diminish the risk of relapse. Upon retrieval, memories become temporarily labile before they reconsolidate in a process that requires protein synthesis. Accumulating evidence suggests that the mammalian target of rapamycin complex 1 (mTORC1), which is responsible for the translation of a subset of dendritic proteins, is crucial for memory reconsolidation. Here, we explored the involvement of two regulatory pathways of mTORC1, namely phosphoinositide 3-kinase (PI3K)-AKT and extracellular regulated kinase1/2 (ERK1/2), in the reconsolidation process in a rat model of non-operant alcohol self-administration. We found that retrieval of alcohol memories using an odor-taste cue increased ERK1/2 activation in the amygdala, but did not affect the PI3K-AKT pathway. Importantly, inhibition of ERK1/2 shortly after alcohol memory retrieval impaired reconsolidation and led to long-lasting suppression of relapse to alcohol drinking. Additionally, we show that attenuation of alcohol memories and relapse was also induced by post-retrieval administration of lacosamide, an inhibitor of collapsin response mediator protein-2 (CRMP2) - a translational product of mTORC1 that is functionally regulated by PI3K-AKT signaling. Together, our findings provide evidence for the crucial role of ERK1/2 and CRMP2 in the reconsolidation of alcohol memories, and mark the FDA-approved drug, lacosamide, as a potential treatment for alcohol use disorder.

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Rahamim, N., Liran, M., Aronovici, C., Flumin, H., Gordon, T., Urshansky, N., Barak, S.. 2023-12-13. ERK1/2 inhibition disrupts alcohol memory reconsolidation and prevents relapse. https://doi.org/10.1101/2023.12.12.571297

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