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Cited by 172Memory and Neural MechanismsMemory Processes and InfluencesNeurotransmitter Receptor Influence on Behavior

Disruption of alcohol-related memories by mTORC1 inhibition prevents relapse

Open access
Barak, Segev, Liu, Feng, Hamida, Sami Ben, Yowell, Quinn V, Neasta, Jeremie, Kharazia, Viktor, Janak, Patricia H, Ron, Dorit·2013·Nature Neuroscience
DOI 10.1038/nn.3439PMC PMC3725202
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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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Crossref · 10.1038/nn.3439

Cites

54 of 54 references verified0 citation errors · 0 not checkable

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Nothing to recompute.

Claims the paper makes

0 of 26 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Omitting the reactivation session eliminates the effect of systemic rapamycin or vehicle administered 24 h before the test.

    “Importantly, in a control experiment we found no effect when the reactivation session was omitted (i.e., rapamycin or vehicle was systemically administered 24 h before the test; Fig. 3E)”
    Quote in the paperSubstantial claim
  • Findingown data

    Relapse to alcohol seeking was completely abolished when mTORC1 was inhibited after retrieving the memory by presentation of the odor-taste cue in the home cage outside the alcohol-associated context.

    “In contrast, we found that relapse to alcohol seeking was completely abolished when mTORC1 was inhibited after retrieving the memory by presentation of the odor-taste cue in the home cage (i.e., outside of the alcohol-associated context)”
    Quote in the paperSubstantial claim
  • Findingown data

    Rapamycin with omission of the reactivation session has no effect on alcohol intake.

    “Specifically, administration of rapamycin with the omission of the reactivation session had no effect on alcohol intake (Fig. 5B)”
    Quote in the paperSubstantial claim
  • Findingown data

    mTORC1 inhibition after memory reactivation with an odor-taste cue in the home cage substantially reduces relapse to alcohol seeking and drinking.

    “Strikingly, mTORC1 inhibition after memory reactivation substantially reduced relapse to alcohol seeking and drinking in this procedure, as indicated by low responding at the retention and reacquisition tests as compared to vehicle-treated subjects (Fig. 5A, left panel).”
    Quote in the paperSubstantial claim
  • Findingown data

    Rapamycin does not induce conditioned place aversion.

    “Finally, we show that rapamycin does not induce conditioned place aversion (Fig. 6)”
    Quote in the paperSubstantial claim
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    After chamber reactivation, rapamycin attenuated response levels, but active lever presses remained higher than inactive lever presses.

    “when we assessed the effects of rapamycin on relapse after memory reactivation in the alcohol self-administration chamber, response levels were attenuated, but were still higher for the active lever compared to the inactive lever.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Sucrose intake was not altered by rapamycin after retrieval of sucrose-related memories or after reactivation of alcohol-associated memories.

    “Specifically, sucrose intake was not altered by rapamycin administration after retrieval of sucrose-related memories or by administration of the inhibitor after reactivation of alcohol-associated memories.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Intra-CeA rapamycin focally inhibits the mTORC1 pathway, reducing phosphorylation of S6, S6K and 4E-BP.

    “We found that intra-CeA infusion of rapamycin (50 μg/side; Suppl. Fig. 4) focally inhibits the mTORC1 pathway as reflected by reduced phosphorylation of S6, S6K and 4E-BP (Suppl. Fig. 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Memory reactivation in the self-administration chamber activated mTORC1 in the PrL and OFC as well as the CeA, while only CeA activation was observed after home-cage reactivation.

    “Memory reactivation in the context of the alcohol self-administration chamber activated mTORC1 signaling in the PrL and OFC as well as the CeA, while only CeA activation was observed after memory reactivation in the home cage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Systemic rapamycin after memory reactivation suppresses alcohol seeking and consumption 24 and 48 h later, reducing active lever presses compared with vehicle.

    “We found that mTORC1 inhibition after memory reactivation suppressed alcohol seeking and consumption, 24 and 48 h later, respectively, as reflected in reduced active lever presses by rats receiving rapamycin compared to vehicle-treated rats (Fig. 3B&C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Upon retrieval, a memory reactivates and undergoes destabilization followed by reconsolidation.

    “Current conceptions of memory processes hold that upon retrieval of the memory it is reactivated, and undergoes a process of destabilization followed by a process of reconsolidation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Nader, K. & Hardt, O. A single standard for memory: the case for reconsolidation. Nat. Rev. Neurosci. 10, 224–234 (2009). source

      Not checked in the free run.

    • cites [6] Dudai, Y. Reconsolidation: the advantage of being refocused. Curr. Opin. Neurobiol. 16, 174–178 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Relapse to alcohol abuse is a critical clinical issue.

    “Most alcoholic patients will relapse within the first year of abstinence3, highlighting relapse as a critical clinical issue.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Sinha, R. New findings on biological factors predicting addiction relapse vulnerability. Curr. Psychiatry Rep. 13, 398–405 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    mTORC1 contributes to reconsolidation of fear and spatial recognition memories.

    “as well as to reconsolidation of fear and spatial recognition memories16-20”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [16] Jobim, P.F. et al. Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory. Neurobiol. Learn. Mem. 97, 105–112 (2012). source

      Not checked in the free run.

    • cites [17] Jobim, P.F. et al. Impairment of object recognition memory by rapamycin inhibition of mTOR in the amygdala or hippocampus around the time of learning or reactivation. Behav. Brain Res. 228, 151–158 (2012). source

      Not checked in the free run.

    • cites [18] Blundell, J., Kouser, M. & Powell, C.M. Systemic inhibition of mammalian target of rapamycin inhibits fear memory reconsolidation. Neurobiol. Learn. Mem. 90, 28–35 (2008). source

      Not checked in the free run.

    • cites [19] Glover, E.M., Ressler, K.J. & Davis, M. Differing effects of systemically administered rapamycin on consolidation and reconsolidation of context vs. cued fear memories. Learn. Mem. 17, 577–581 (2010). source

      Not checked in the free run.

    • cites [20] Gafford, G.M., Parsons, R.G. & Helmstetter, F.J. Consolidation and reconsolidation of contextual fear memory requires mammalian target of rapamycin-dependent translation in the dorsal hippocampus. Neuroscience 182, 98–104 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mTORC1 is implicated in synaptic plasticity and memory processes.

    “and is implicated in synaptic plasticity12, 13, as well as in memory processes12.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Hoeffer, C.A. & Klann, E. mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33, 67–75 (2010). source

      Not checked in the free run.

    • cites [13] Stoica, L. et al. Selective pharmacogenetic inhibition of mammalian target of rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage. Proc. Natl. Acad. Sci. USA 108, 3791–3796 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    After 7 weeks of training, rats achieved a stable baseline alcohol consumption of 5.5-6.5 g/kg per 24 h.

    “After obtaining a stable baseline alcohol consumption level (5.5-6.5 g/kg/24 h; Figure 4)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No statistical test was used to determine sample size before the study.

    “No statistical test was run to determine sample size a priori.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Study design and conductnone given

    The sample sizes used in this study were similar to those used in previous publications.

    “The sample sizes we chose are similar to those used in previous publications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Rapamycin disrupts memory reconsolidation rather than merely the motivation to respond or consume alcohol.

    “This finding indicates that rapamycin disrupts memory reconsolidation, rather than merely the motivation to respond or consume alcohol.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Rapamycin disrupts reconsolidation of these memories, resulting in long-lasting suppression of relapse.

    “Importantly, we present data that the mTORC1 inhibitor, rapamycin, disrupts the reconsolidation of these memories, resulting in a long-lasting suppression of relapse.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The memory lability period after reactivation is limited to a few hours of the reconsolidation window; after that, reconsolidation completes and memories become stable and resistant to mTORC1 inhibition.

    “These results suggest that the memory lability period following its reactivation is limited to a few hours of the “reconsolidation window”, after which the memory reconsolidation process is completed, and the memories become stable4, 5 and resistant to mTORC1 inhibition.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Milton, A. Drink, drugs and disruption: memory manipulation for the treatment of addiction. Curr. Opin. Neurobiol. published online, http://dx.doi.org/10.1016/j.conb.2012.11.008 (21 December 2012). source

      Not checked in the free run.

    • cites [5] Nader, K. & Hardt, O. A single standard for memory: the case for reconsolidation. Nat. Rev. Neurosci. 10, 224–234 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The amnestic actions of rapamycin are specific for reactivated memories while other memories remain intact.

    “indicating that the amnestic actions of rapamycin are specific for the reactivated memories, while other memories remain intact (Suppl. Fig. 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    mTORC1 activation within the CeA is required for reconsolidation of alcohol-associated memories, likely via mTORC1-dependent de novo protein synthesis.

    “Together, these data suggest that mTORC1 activation within the CeA is required for reconsolidation of alcohol-associated memories, a process that is likely to be mediated via mTORC1-dependent de novo protein synthesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Some instrumental associations may not be susceptible to reconsolidation disruption, accounting for the low level of responding that remained.

    “hence some instrumental associations may not be susceptible to reconsolidation disruption, accounting for the low level of responding that remained.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Counts of pS6-positive cells were performed blind to treatment group.

    “All counts were performed blind with respect to treatment groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Additional associations related to the instrumental lever-press response and contextual modulation are likely also retrieved, accounting for cortical activation.

    “Thus, additional associations related to the instrumental lever-press response and the contextual modulation of those associations are likely also retrieved, accounting for the activation of these cortical regions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The reduction in relapse is observed even 14 days after memory reactivation and cannot be attributed to taste aversion or devaluation of the outcome.

    “Furthermore, our findings that the reduction in relapse is observed even 14 days after the memory reactivation, and that this effect cannot be attributed to taste aversion or devaluation of the outcome, further highlights the translational potential of this relapse prevention approach.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The reconsolidation of alcohol-associated memories depends on mTORC1 activation, and inhibiting this pathway attenuates the memories and reduces relapse.

    “This finding indicates that mTORC1 activation is required for reconsolidation of alcohol-related memories, and that by inhibiting this pathway, the memories can be attenuated and relapse can be reduced.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Three conditioning sessions were used because 3 to 4 sessions are generally needed to produce robust place preference or aversion to rewarding substances, including drugs of abuse, in rodents.

    “Three conditioning sessions were chosen as 3 to 4 sessions are generally used to obtain robust placed preference or aversion to rewarding substances, including drugs of abuse, in rodents9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Milton, A.L. et al. Antagonism at NMDA receptors, but not β-adrenergic receptors, disrupts the reconsolidation of pavlovian conditioned approach and instrumental transfer for ethanol-associated conditioned stimuli. Psychopharmacology (Berl.) 219, 751–761 (2012). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Reconsolidation depends on de novo protein translation.

    “However, while the dependence of reconsolidation on de novo protein translation is established10, 11”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Miller, C.A. & Sweatt, J.D. Amnesia or retrieval deficit? Implications of a molecular approach to the question of reconsolidation. Learn. Mem. 13, 498–505 (2006). source

      Not checked in the free run.

    • cites [11] Nader, K., Schafe, G.E. & Le Doux, J.E. Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature 406, 722–726 (2000). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Microinjections began only after self-administration responding returned to pre-surgery baseline.

    “Microinjections began when self-administration responding retuned to pre-surgery baseline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    mTORC1 inhibition disrupts memories associated with alcohol but not with the natural reinforcer sucrose.

    “indicating that mTORC1 inhibition is effective in disrupting memories associated with alcohol, but not with other, natural reinforcers.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Only rats with cannula placements verified within the central nucleus of the amygdala were included in the analysis.

    “Only data from subjects with cannulae located within the CeA were included in the analysis (Suppl. Fig 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Effective reactivation of alcohol-associated memories is achieved by a brief presentation of alcohol odor and taste, and mTORC1 inhibition disrupts these memories and suppresses relapse, with translational implications for preventing relapse in alcoholism.

    “Our present results show that effective reactivation of alcohol-associated memories is achieved by a brief presentation of alcohol’s odor and taste, and that mTORC1 inhibition disrupts these memories and suppresses relapse”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Alcohol-related memories in rats are a valid model for human alcohol relapse and for translational conclusions about alcohol use disorders.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    After 4-5 weeks of fixed ratio 3 training, rats had stable response and alcohol consumption levels.

    “After 4-5 weeks of training in FR3, when a stable response and alcohol consumption levels were obtained”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The left-right placement of the alcohol and water bottles was alternated across sessions to control for side preference.

    “The placement (left or right) of each solution was alternated between each session to control for side preference.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The alcohol-selectivity demonstrated here has translational implications, potentially enabling selective interference with alcohol-related memories while leaving non-alcohol memories intact.

    “Importantly, the alcohol-selectivity we demonstrate here has direct translational implications, potentially enabling selective interference with alcohol-related memories while leaving non-alcohol memories (e.g., natural rewards memories) intact.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Alcohol-related memories in rats are a valid model for human alcohol relapse and for translational conclusions about alcohol use disorders.

  • Classified as probably not a substantial claim.

    Premisecitation

    mTORC1 contributes to memory processes involved in cocaine-conditioned place preference and cue-induced reinstatement.

    “Interestingly, mTORC1 is reported to contribute to memory processes involved in cocaine-conditioned place preference and cue-induced reinstatement14, 15”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Wang, X. et al. Nucleus accumbens core mammalian target of rapamycin signaling pathway is critical for cue-induced reinstatement of cocaine seeking in rats. J. Neurosci. 30, 12632–12641 (2010). source

      Not checked in the free run.

    • cites [15] Bailey, J., Ma, D. & Szumlinski, K.K. Rapamycin attenuates the expression of cocaine-induced place preference and behavioral sensitization. Addict. Biol. 17, 248–258 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The odor and taste of alcohol are potent cues that evoke memory reconsolidation independently of the training context, enabling complete abolition of relapse by mTORC1 inhibition.

    “These findings demonstrate that the odor and taste of alcohol are potent cues that evoke memory reconsolidation, independently of the training context, enabling a complete abolition of relapse to alcohol seeking by mTORC1 inhibition.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Rats achieved a stable baseline of operant performance for 20% alcohol under a fixed ratio 3 schedule in 30-min sessions, 5 days per week.

    “leading to a stable baseline of operant performance to obtain the delivery of 0.1 ml of a 20% alcohol solution under a fixed ratio 3 (FR3) schedule, during 30 min sessions, 5 days per week.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    After 7 weeks of intermittent access, rats maintained a stable baseline of alcohol consumption of 5.5-6 g/kg per 24 h.

    “when rats maintained a stable baseline of alcohol consumption of 5.5-6 g/kg/24 h.”
    Quote in the paperNot a substantial claim
35 of 35

  • The paper relies on this without support.

    The specific signaling molecules and proteins required for drug memory reconsolidation, especially for alcohol, remain largely unknown.

    “However, while the dependence of reconsolidation on de novo protein translation is established10, 11, the specific signaling molecules and proteins that are required for drug memory reconsolidation remains largely unknown, especially for alcohol.”

  • The paper relies on this without support.

    Alcohol-related memories in rats are a valid model for human alcohol relapse and for translational conclusions about alcohol use disorders.

    “Our findings provide evidence that the mTORC1 pathway and its downstream substrates play a crucial role in alcohol-related memory reconsolidation, and highlight this pathway as a therapeutic target to prevent relapse.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Blockade of mTORC1 systemically blocked reconsolidation of cocaine memories, and blockade in the amygdala blocked reconsolidation of alcohol memories, suggesting a potential molecular target for relapse treatment.

    “Even more compelling, blockade of the mTORC1 pathway systemically blocked the reconsolidation of cocaine memories,150 and blockade of mTORC1 in the amygdala blocked the reconsolidation of alcohol memories;151 these results suggest a potential molecular target for the treatment of relapse.”

    From Neurobiology of addiction: a neurocircuitry analysis (2016) · cites this paper as [151]

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Authors
Barak, S., Liu, F., Hamida, S. B., Yowell, Q. V., Neasta, J., Kharazia, V., Janak, P. H., & Ron, D.
Affiliations
  • Tel Aviv University (IL)
  • University of California, San Francisco (US)
Corresponding author
Janak, Patricia H
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2013-06-23
Volume
16
Issue
8
Pages
1111-1117
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.3439
PMC
PMC3725202
OpenAlex
W2093405266
Cited by
172
References
54
Citations by year
2026: 2 · 2025: 2 · 2024: 7 · 2023: 11 · 2022: 8 · 2021: 16 · 2020: 15 · 2019: 22 · 2018: 13 · 2017: 16 · 2016: 21 · 2015: 8 · 2014: 20 · 2013: 10
FWCI
10.79
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Institute on Alcohol Abuse and Alcoholism (P50AA017072)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
alcohol relapse, memory reconsolidation, mTORC1, rapamycin, central amygdala, synaptic proteins, memory disruption, alcoholism treatment, protein synthesis-dependent memory
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Ethanol, Amygdala, Animals, Anisomycin, Conditioning, Operant, Cues, Male, Memory, Nerve Tissue Proteins, Neuronal Plasticity, Odorants, Phosphorylation, Protein Processing, Post-Translational, Spatial Behavior, Taste, Protein Biosynthesis, Signal Transduction, Prefrontal Cortex, Sirolimus, Rats, Long-Evans, Multiprotein Complexes, Rats, TOR Serine-Threonine Kinases, Binge Drinking

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