eIF2  Dephosphorylation in Basolateral Amygdala Mediates Reconsolidation of Drug Memory

Abstract

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 ␣-subunit (eIF2␣) 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 eIF2␣ dephosphorylation is required for the reconsolidation of morphine and cocaine memories in rats. We found that the levels of eIF2␣ 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 eIF2␣ 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 eIF2␣ 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 eIF2␣ dephosphorylation in the BLA mediates the memory reconsolidation of drug-paired stimuli.

AMPK Signaling in the Dorsal Hippocampus Negatively Regulates Contextual Fear Memory Formation

“…The experimental procedures that were used for the virus injections were based on previous studies (Jian et al, 2014;Minokoshi et al, 2004). The rats were anesthetized with sodium pentobarbital.…”

“…Crude cytoplasmic and synaptosomal membrane fractions were collected based on our previous studies (Chai et al, 2014;Jian et al, 2014;Liu et al, 2014;Lu et al, 2005). After decapitation, the brains were rapidly extracted and frozen in − 60°C N-hexane.…”

“…The locations of the cannulae are shown in Figures 2b and 3b. In addition, the brains were coronally sectioned at 20 μm using a sliding microtome, and the brain slices were counterstained with DAPI and examined using an Olympus IX83 fluorescent microscope to evaluate eGFP expression in the CA1 and CA3 (Jian et al, 2014).…”

Inhibition of protein synthesis but not β-adrenergic receptors blocks reconsolidation of a cocaine-associated cue memory

“…Reconsolidation blockade, conversely, is thought to directly alter and/or update the original memory, leading to a long-lasting, context-independent change and, thus, to provide potentially superior relapse prevention (Lee et al 2005;Milekic et al 2006;Sanchez et al 2010). Interfering with memory reconsolidation in rodents has been shown to block memories related to a number of drugs, including morphine (Valjent et al 2006;Taubenfeld et al 2010), ethanol (Wouda et al 2010;Schramm et al 2015), nicotine (Fang et al 2011;Tedesco et al 2014), methamphetamine (Zhao et al 2011b;Yu et al 2013), amphetamine (Sadler et al 2007;Contreras et al 2012), heroin (Hellemans et al 2006;Jian et al 2014), and cocaine (Milton et al 2008;Sanchez et al 2010). Notably, manipulations of memory reconsolidation have also been reported to decrease the strength of drug-related memories in humans (Zhao et al 2011a;Saladin et al 2013).…”

Hijacking translation in addiction

“…As with all important discoveries, these new findings raise a number of questions. For example, are the effects of eIF2α in addiction specific to the VTA, or are other regions of the brain involved (Jian et al, 2014)? Does eIF2α also affect other aspects of addiction such as relapse?…”