Reactivation of cocaine reward memory engages the Akt/GSK3/mTOR signaling pathway and can be disrupted by GSK3 inhibition
Open accessAbstract
RATIONAL: Memories return to a labile state following their retrieval and must undergo a process of reconsolidation to be maintained. Thus, disruption of cocaine reward memories by interference with reconsolidation may be therapeutically beneficial in the treatment of cocaine addiction. OBJECTIVE: The objectives were to elucidate the signaling pathway involved in reconsolidation of cocaine reward memory and to test whether targeting this pathway could disrupt cocaine-associated contextual memory. METHODS: Using a mouse model of conditioned place preference, regulation of the activity of glycogen synthase kinase-3 (GSK3), mammalian target of Rapamycin complex 1 (mTORC1), P70S6K, β-catenin, and the upstream signaling molecule Akt, was studied in cortico-limbic-striatal circuitry after re-exposure to an environment previously paired with cocaine. RESULT: Levels of phosporylated Akt-Thr308, GSK3α-Ser21, GSK3β-Ser9, mTORC1, and P70S6K were reduced in the nucleus accumbens and hippocampus 10 min after the reactivation of cocaine cue memories. Levels of pAkt and pGSK3 were also reduced in the prefrontal cortex. Since reduced phosphorylation of GSK3 indicates heightened enzyme activity, the effect of a selective GSK3 inhibitor, SB216763, on reconsolidation was tested. Administration of SB216763 immediately after exposure to an environment previously paired with cocaine abrogated a previously established place preference, suggesting that GSK3 inhibition interfered with reconsolidation of cocaine-associated reward memories. CONCLUSIONS: These findings suggest that the Akt/GSK3/mTORC1 signaling pathway in the nucleus accumbens, hippocampus, and/or prefrontal cortex is critically involved in the reconsolidation of cocaine contextual reward memory. Inhibition of GSK3 activity during memory retrieval can erase an established cocaine place preference.
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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 [150]
The Methods and Results report that systemic injection of the GSK3 inhibitor SB216763 after memory reactivation disrupted reconsolidation of cocaine reward memory. They do not report systemic blockade of mTORC1; the Discussion describes reduced mTORC1 phosphorylation after memory reactivation, not an mTORC1-blockade experiment. The alcohol-memory finding has a separate citation in the citing sentence and is not attributed to this paper. (LLM, conf=0.88)
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Neurobiology of addiction: a neurocircuitry analysis
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- Authors
- Shi, X., Miller, J. S., Harper, L. J., Poole, R. L., Gould, T. J., & Unterwald, E. M.
- Affiliations
- Temple University (US)
- Corresponding author
- Unterwald, Ellen M.
- Venue
- Psychopharmacology
- Published
- 2014-03-05
- Volume
- 231
- Issue
- 16
- Pages
- 3109-3118
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- PMC
- PMC4110417
- OpenAlex
- W2086913117
- Cited by
- 79
- References
- 52
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 2 · 2023: 6 · 2022: 7 · 2021: 6 · 2020: 10 · 2019: 9 · 2018: 11 · 2017: 6 · 2016: 8 · 2015: 6
- FWCI
- 3.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Psychopharmacology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DA013429, DA07237)
- National Institute on Drug Abuse (P30-DA13429, DA13429, DA 013429, P30DA013429, T32DA 07237, DA 07237, R01 DA09580, R01DA009580, T32DA007237)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Keywords
- memory reconsolidation, glycogen synthase kinase-3 inhibition, SB216763, conditioned place preference, nucleus accumbens, hippocampus, prefrontal cortex, p70S6K, β-catenin, cocaine dependence, memory retrieval
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Animals, Conditioning, Operant, Cues, Enzyme Inhibitors, Fear, Hippocampus, Indoles, Limbic System, Male, Maleimides, Memory, Phosphorylation, Reward, Signal Transduction, Neostriatum, Prefrontal Cortex, Cocaine-Related Disorders, Glycogen Synthase Kinase 3, Multiprotein Complexes, Oncogene Protein v-akt, Mice, TOR Serine-Threonine Kinases
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