Exposure to a heroin-associated conditioned stimulus can reactivate drug reward memory, trigger drug cravings, and induce relapse in heroin addicts. The amygdala, a brain region related to emotions and motivation, is involved in processing rewarding stimulus. Recent evidence demonstrated that disrupting the reconsolidation of the heroin drug memories attenuated heroin seeking which was associated with the basolateral amygdala (BLA). Meanwhile, neural functions associated with learning and memory, like synaptic plasticity, are regulated by glycogen synthase kinase 3 beta (GSK-3β). In addition, GSK-3β regulated memory processes, like retrieval and reconsolidation of cocaine-induced memory. Here, we used a heroin intravenous self-administration (SA) paradigm to illustrate the potential role of GSK-3β in the reconsolidation of drug memory. Therefore, we used SB216763 as a selective inhibitor of GSK-3β. We found that injecting the selective inhibitor SB216763 into the BLA, but not the central amygdala (CeA), immediately after heroin-induced memory retrieval disrupted reconsolidation of heroin drug memory and significantly attenuated heroin-seeking behavior in subsequent drug-primed reinstatement, suggesting that GSK-3β is critical for reconsolidation of heroin drug memories and inhibiting the activity of GSK-3β in BLA disrupted heroin drug memory and reduced relapse. However, no retrieval or 6 h after retrieval, administration of SB216763 into the BLA did not alter heroin-seeking behavior in subsequent heroin-primed reinstatement, suggesting that GSK-3β activity is retrieval-dependent and time-specific. More importantly, a long-term effect of SB216763 treatment was observed in a detectable decrease in heroin-seeking behavior, which lasted at least 28 days. All in all, this present study demonstrates that the activity of GSK-3β in BLA is required for reconsolidation of heroin drug memory, and inhibiting GSK-3β activity of BLA disrupts reconsolidation and attenuates heroin relapse.

Drug abuse is considered a maladaptive pathology of emotional memory and is associated with craving and relapse induced by drug-associated stimuli or drugs. Reconsolidation is an independent memory process with a strict time window followed by the reactivation of drug-associated stimulus depending on the basolateral amygdala (BLA). Pharmacology or behavior treatment that disrupts the reconsolidation can effectively attenuate drug-seeking in addicts. Here, we hypothesized that heroin-memory reconsolidation requires cAMP-dependent protein kinase A (PKA) of BLA based on the fundamental effect of PKA in synaptic plasticity and memory process. After 10 days of acquisition, the rats underwent 11 days of extinction training and then received the intra-BLA infusions of the PKA inhibitor Rp-cAMPS at different time windows with/without a reactivation session. The results show that PKA inhibitor treatment in the reconsolidation time window disrupts the reconsolidation and consequently reduces cue-induced reinstatement, heroin-induced reinstatement, and spontaneous recovery of heroin-seeking behavior in the rats. In contrast, there was no effect on cue-induced reinstatement in the intra-BLA infusion of PKA inhibitor 6 h after reactivation or without reactivation. These data suggest that PKA inhibition disrupts the reconsolidation of heroin-associated memory, reduces subsequent drug seeking, and prevents relapse, which is retrieval-dependent, time-limited, and BLA-dependent.

Substance use disorders (SUDs) precipitate a loss of control over substance use, thus compromising daily functioning and social behavior. Current addiction treatment relies primarily on medication. Relapses may occur after extended periods of abstinence upon exposure to substance-associated stimuli or environments. More must be done to prevent relapsing. Deep brain stimulation (DBS) is used to treat a spectrum of medical conditions through insertion of electrodes into specific brain regions and administration of impulses that regulate brain activity. Considerable evidence suggests that DBS may be helpful in treating addiction, but the targets and treatment parameters remain ambiguous. This review describes research progress and the associated targets of DBS in managing alcohol, cocaine, opioid, and nicotine addiction, to lay groundwork for future research. It additionally examines the risks and safety aspects of DBS in SUD treatment, to optimize DBS for enhanced clinical efficacy in managing addictive disorders.