Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse

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Abstract

Relapse to alcohol abuse is an important clinical issue that is frequently caused by cue-induced drug craving. Therefore, disruption of the memory for the cue-alcohol association is expected to prevent relapse. It is increasingly accepted that memories become labile and erasable soon after their reactivation through retrieval during a memory reconsolidation process that depends on protein synthesis. Here we show that reconsolidation of alcohol-related memories triggered by the sensory properties of alcohol itself (odor and taste) activates mammalian target of rapamycin complex 1 (mTORC1) in select amygdalar and cortical regions in rats, resulting in increased levels of several synaptic proteins. Furthermore, systemic or central amygdalar inhibition of mTORC1 during reconsolidation disrupts alcohol-associated memories, leading to a long-lasting suppression of relapse. Our findings provide evidence that the mTORC1 pathway and its downstream substrates are crucial in alcohol-related memory reconsolidation and highlight this pathway as a therapeutic target to prevent relapse.

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Figure 1: The mTORC1 signaling pathway is activated in the CeA, mPFC and OFC after reactivation of alcohol-associated memories.
Figure 2: Reactivation of alcohol-associated memories increases the levels of synaptic proteins.
Figure 3: Inhibition of mTORC1 after reactivation of alcohol-associated memories attenuates relapse measured as instrumental responding for alcohol.
Figure 4: Infusion of rapamycin or anisomycin into the CeA after reactivation of alcohol-associated memories attenuates relapse.
Figure 5: Inhibition of mTORC1 after reactivation of alcohol-associated memories in the home cage induces a potent, long-term suppression of relapse.
Figure 6: Rapamycin does not induce place aversion.

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Acknowledgements

This work was supported by US National Institutes of Health National Institute on Alcohol Abuse and Alcoholism grant P50 AA017072 (D.R. and P.H.J.) and funds from the State of California for Medical Research on Alcohol and Substance Abuse through the University of California, San Francisco (D.R. and P.H.J.). We thank S. Carnicella for critical review of the manuscript.

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S.B., J.N., P.H.J. and D.R. designed the research. S.B., F.L., Q.V.Y., S.B.H., J.N. and V.K. performed the research. S.B., F.L., S.B.H., Q.V.Y., J.N. and D.R. analyzed data. S.B., P.H.J. and D.R. wrote the paper.

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Correspondence to Patricia H Janak or Dorit Ron.

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The authors declare no competing financial interests.

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Barak, S., Liu, F., Hamida, S. et al. Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse. Nat Neurosci 16, 1111–1117 (2013). https://doi.org/10.1038/nn.3439

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