eIF2 Dephosphorylation in Basolateral Amygdala Mediates Reconsolidation of Drug Memory

• DOI: 10.1523/jneurosci.0934-14.2014
• Publication Date: 2014-07-23T17:00:04Z
• Authors: M. Jian; Y.-X. Luo; Y.-X. Xue; Y. Han; H.-S. Shi; J.-F. Liu; W. Yan; P. Wu; S.-Q. Meng; J.-H. Deng; H.-W. Shen; J. Shi; L. Lu
• Keywords: Male; 0301 basic medicine; Morphine; Drug-Seeking Behavior; Eukaryotic Initiation Factor-2; Self Administration; Amygdala; Rats; Heroin; Rats, Sprague-Dawley; 03 medical and health sciences; Cocaine; Memory; Animals; Cues; Phosphorylation

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.