Basolateral amygdala is required for reconsolidation updating of heroin‐associated memory after prolonged withdrawal

Abstract

Postretrieval extinction procedures are effective nonpharmacological interventions for disrupting drug‐associated memories. Nonetheless, the conditioned stimulus (CS) memory retrieval‐extinction procedure is ineffective in inhibiting drug craving and relapse after prolonged withdrawal, which significantly undermines its therapeutic potential. In the present study, we showed that, unlike the CS memory retrieval‐extinction procedure, noncontingent heroin injections (unconditioned stimulus [UCS]) 1 hour before the extinction sessions decreased the heroin‐priming‐induced reinstatement, renewal, and spontaneous recovery of heroin seeking after 28 days of withdrawal (ie, remote heroin‐associated memories) in rats. The UCS retrieval manipulation induced reactivation of the basolateral amygdala (BLA) after prolonged withdrawal, and this reactivation was absent with the CS retrieval manipulation. Chemogenetic inactivation of the BLA abolished the inhibitory effect of the UCS memory retrieval‐extinction procedure on heroin‐priming‐induced reinstatement after prolonged withdrawal. Furthermore, the combination of chemogenetic reactivation of BLA and CS retrieval‐extinction procedure resembled the inhibitory effect of UCS retrieval‐extinction procedure on heroin seeking after prolonged withdrawal. We also observed that the inhibitory effect of the UCS retrieval‐extinction procedure is mediated by regulation of AMPA receptor endocytosis in the BLA. Our results demonstrate critical engagement of the BLA in reconsolidation updating of heroin‐associated memory after prolonged withdrawal, extending our knowledge of the boundary conditions of the reconsolidation of drug‐associated memories.

Glutamatergic Systems and Memory Mechanisms Underlying Opioid Addiction

“…Conversely, artificially activating glutamatergic BLA neurons during remote memory retrieval facilitates the destabilization of remote heroin memories, and restores the ability of weaker conditioned drug cues to initiate heroin memory reconsolidation. Collectively, these data suggest that remote memories for opioid reinforcement are at least in part stored in the BLA, and that modification of these opioid memories depends on synaptic neuroadaptations and neuronal activity in this structure (Yuan et al 2019). In addition to AMPAR, NMDARs are also required for the reconsolidation of morphine CPP memories (Zhai et al 2008).…”

“…Evidence suggests that after protracted withdrawal from heroin self-administration when memories are remote as opposed to recent, retrieval-extinction procedures are less effective. If instead of drug-conditioned cues, the unconditioned stimulus, heroin, is used to trigger memory retrieval, remote drug memories can again become labile and susceptible to interference by retrievalextinction procedures (Yuan et al 2019). This process may be mediated by the ability of drugs to temporarily reverse withdrawal-induced changes in glutamatergic synapses (Jedynak et al 2016;Spencer et al 2017;Madayag et al 2019).…”

Inhibition of Glycogen Synthase Kinase 3β Activity in the Basolateral Amygdala Disrupts Reconsolidation and Attenuates Heroin Relapse

“…Inhibiting activity of GSK-3β in the BLA, but not the CeA, effectively disrupted reconsolidation of heroin cue memory and blocked subsequent drug-seeking behaviors. Many studies have demonstrated that BLA is involved in memory reconsolidation ( Wells et al, 2013 ; Yuan et al, 2020 ). However, the spcefic mechanism of GSK-3β in drug memory reconsolidation remains to be elucidated.…”

Pi4KIIα Regulates Unconditioned Stimulus-Retrieval-Induced Fear Memory Reconsolidation through Endosomal Trafficking of AMPA Receptors

“…This discrepancy may reflect distinct retrieval paradigms. Indeed, US retrieval has been shown to activate more memory traces and stronger protein alterations than CS retrieval (Liu et al, 2014;Xue et al, 2017;Yuan et al, 2019). Furthermore, we found that the pharmacological inhibition of Pi4KIIa in the BLA decreased GluA1 levels 1 h after US retrieval, and the genetic knockdown of Pi4KIIa impaired the enhancement of mEPSC frequency that was induced by US retrieval, suggesting a regulatory role for Pi4KIIa in GluA1 surface expression and synaptic efficacy in the rat BLA.…”