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      eIF2α Dephosphorylation in Basolateral Amygdala Mediates Reconsolidation of Drug Memory


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          Maladaptive memories elicited by exposure to environmental stimuli associated with drugs of abuse are often responsible for relapse among addicts. Interference with the reconsolidation of drug memory can inhibit drug seeking. Previous studies have indicated that the dephosphorylation of the eukaryotic initiation factor 2 α-subunit (eIF2α) plays an important role in synaptic plasticity and long-term memory consolidation, but its role in the reconsolidation of drug memory remains unknown. The amygdala is required for the reconsolidation of a destabilized drug memory after retrieval of drug-paired stimuli. Here, we used conditioned place preference (CPP) and self-administration procedures to determine whether amygdala eIF2α dephosphorylation is required for the reconsolidation of morphine and cocaine memories in rats. We found that the levels of eIF2α phosphorylation (Ser51) and activating transcription factor 4 (ATF4) were decreased after reexposure to a previously morphine- or cocaine-paired context (i.e., a memory retrieval procedure) in the basolateral amygdala (BLA) but not in the central amygdala. Intra-BLA infusions of Sal003, a selective inhibitor of eIF2α dephosphorylation, immediately after memory retrieval disrupted the reconsolidation of morphine- or cocaine-induced CPP, leading to a long-lasting suppression of drug-paired stimulus-induced craving. Advanced knockdown of ATF4 expression in the BLA by lentivirus-mediated short-hairpin RNA blocked the disruption of the reconsolidation of morphine-induced CPP induced by Sal003 treatment. Furthermore, inhibition of eIF2α dephosphorylation in the BLA immediately after light/tone stimulus retrieval decreased subsequent cue-induced heroin-seeking behavior in the self-administration procedure. These results demonstrate that eIF2α dephosphorylation in the BLA mediates the memory reconsolidation of drug-paired stimuli.

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          Author and article information

          J Neurosci
          J. Neurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          23 July 2014
          : 34
          : 30
          : 10010-10021
          1Institute of Mental Health/Peking University Sixth Hospital and Key Laboratory of Mental Health and
          2National Institute on Drug Dependence, Peking University, Beijing 100191, China,
          3Department of Biochemistry and Molecular Biology, Basic Medical College, Hebei Medical University, Shijiazhuang 050017, China, and
          4Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
          Author notes
          Correspondence should be addressed to either of the following: Prof. Lin Lu, Institute of Mental Health, Peking University; 51, Huayuan Bei Road, Beijing 100191, China, linlu@ 123456bjmu.edu.cn ; or Prof. Jie Shi, National Institute on Drug Dependence, Peking University; 38 Xueyuan Road, Beijing 100191, China, Shijie@ 123456bjmu.edu.cn

          Author contributions: L.L., M.J., Y.-X.L., H.-W.S., and J.S. designed research; M.J., Y.-X.L., Y.H., H.-S.S., J.-F.L., and W.Y. performed research; L.L., M.J., and Y.-X.L. contributed unpublished reagents/analytic tools; L.L., M.J., Y.-X.L., and P.W. analyzed data; L.L., M.J., Y.-X.L., Y.-X.X., S.-Q.M., and J.-H.D. wrote the paper.

          *M.J. and Y.-X.L. contributed equally to this work.

          PMC6608301 PMC6608301 6608301 0934-14
          Copyright © 2014 the authors 0270-6474/14/3410010-12$15.00/0


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