Retrieval Of Extinction Memory Research Articles

Memory Reconsolidation Updating in Substance Addiction: Applications, Mechanisms, and Future Prospects for Clinical Therapeutics.

Persistent and maladaptive drug-related memories represent a key component in drug addiction. Converging evidence from both preclinical and clinical studies has demonstrated the potential efficacy of the memory reconsolidation updating procedure (MRUP), a non-pharmacological strategy intertwining two distinct memory processes: reconsolidation and extinction-alternatively termed "the memory retrieval-extinction procedure". This procedure presents a promising approach to attenuate, if not erase, entrenched drug memories and prevent relapse. The present review delineates the applications, molecular underpinnings, and operational boundaries of MRUP in the context of various forms of substance dependence. Furthermore, we critically examine the methodological limitations of MRUP, postulating potential refinement to optimize its therapeutic efficacy. In addition, we also look at the potential integration of MRUP and neurostimulation treatments in the domain of substance addiction. Overall, existing studies underscore the significant potential of MRUP, suggesting that interventions predicated on it could herald a promising avenue to enhance clinical outcomes in substance addiction therapy.

Replication study on the role of dopamine-dependent prefrontal reactivations in human extinction memory retrieval

Even after successful extinction, conditioned fear can return. Strengthening the consolidation of the fear-inhibitory safety memory formed during extinction is one way to counteract return of fear. In a previous study, we found that post-extinction L-DOPA administration improved extinction memory retrieval 24 h later. Furthermore, spontaneous post-extinction reactivations of a neural activation pattern evoked in the ventromedial prefrontal cortex (vmPFC) during extinction predicted extinction memory retrieval, L-DOPA increased the number of these reactivations, and this mediated the effect of L-DOPA on extinction memory retrieval. Here, we conducted a preregistered replication study of this work in healthy male participants. We confirm that spontaneous post-extinction vmPFC reactivations predict extinction memory retrieval. This predictive effect, however, was only observed 90 min after extinction, and was not statistically significant at 45 min as in the discovery study. In contrast to our previous study, we find no evidence that L-DOPA administration significantly enhances retrieval and that this is mediated by enhancement of the number of vmPFC reactivations. However, additional non-preregistered analyses reveal a beneficial effect of L-DOPA on extinction retrieval when controlling for the trait-like stable baseline levels of salivary alpha-amylase enzymatic activity. Further, trait salivary alpha-amylase negatively predicts retrieval, and this effect is reduced by L-DOPA treatment. Importantly, the latter findings result from non-preregistered analyses and thus further investigation is needed.

Hydrocortisone Differentially Affects Reinstatement of Pain-related Responses in Patients With Chronic Back Pain and Healthy Volunteers

Despite the crucial role of effective and sustained extinction of conditioned pain-related fear in cognitive-behavioral treatment approaches for chronic pain, experimental research on extinction memory retrieval in chronic pain remains scarce. In healthy populations, extinction efficacy of fear memory is affected by stress. Therefore, we investigated the effects of oral hydrocortisone administration on the reinstatement of pain-related associations in 57 patients with non-specific chronic back pain (CBP) and 59 healthy control (HC) participants in a differential pain-related conditioning paradigm within a placebo-controlled, randomized, and double-blind design. Participants’ skin conductance responses indicate hydrocortisone-induced reinstatement effects in HCs but no observable reinstatement in HCs receiving placebo treatment. Interestingly, these effects were reversed in patients with CBP, that is, reinstatement responses were only observed in the placebo and not in the hydrocortisone group. Our findings corroborate previous evidence of stress-induced effects on extinction efficacy and reinstatement of fear memory in HCs, extending them into the pain context, and call for more research to clarify the role of stress in fear extinction and return of fear phenomena possibly contributing to treatment failure in chronic pain treatment. PerspectiveOpposing effects in HCs and patients with non-specific CBP may be associated with changes in the patients’ stress systems. These findings could be of relevance to optimizing psychological, extinction-based treatment approaches.

The impact of physical exercise on the consolidation of fear extinction memories.

Based on the mechanisms of fear extinction, exposure therapy is the most common treatment for anxiety disorders. However, extinguished fear responses can reemerge even after successful treatment. Novel interventions enhancing exposure therapy efficacy are therefore critically needed. Physical exercise improves learning and memory and was also shown to enhance extinction processes. This study tested whether physical exercise following fear extinction training improves the consolidation of extinction memories. Sixty healthy men underwent a differential fearconditioning paradigm with fear acquisition training on day 1 and fear extinction training followed by an exercise or resting control intervention on day 2. On day 3, retrieval and reinstatement were tested including two additional but perceptually similar stimuli to explore the generalization of exercise effects. Exercise significantly increased heart rate, salivary alpha amylase, and cortisol, indicating successful exercise manipulation. Contrary to our expectations, exercise did not enhance but rather impaired extinction memory retrieval on the next day, evidenced by significantly stronger differential skin conductance responses (SCRs) and pupil dilation (PD). Importantly, although conditioned fear responses were successfully acquired, they did not fully extinguish, explaining why exercise might have boosted the consolidation of the original fear memory trace instead. Additionally, stronger differential SCRs and PD toward the novel stimuli suggest that the memory enhancing effects of exercise also generalized to perceptually similar stimuli. Together, these findings indicate that physical exercise can facilitate both the long-term retrievability and generalization of extinction memories, but presumably only when extinction was successful in the first place.

Fear extinction relies on ventral hippocampal safety codes shaped by the amygdala.

Extinction memory retrieval is influenced by spatial contextual information that determines responding to conditioned stimuli (CS). However, it is poorly understood whether contextual representations are imbued with emotional values to support memory selection. Here, we performed activity-dependent engram tagging and in vivo single-unit electrophysiological recordings from the ventral hippocampus (vH) while optogenetically manipulating basolateral amygdala (BLA) inputs during the formation of cued fear extinction memory. During fear extinction when CS acquire safety properties, we found that CS-related activity in the vH reactivated during sleep consolidation and was strengthened upon memory retrieval. Moreover, fear extinction memory was facilitated when the extinction context exhibited precise coding of its affective zones. Last, these activity patterns along with the retrieval of the fear extinction memory were dependent on glutamatergic transmission from the BLA during extinction learning. Thus, fear extinction memory relies on the formation of contextual and stimulus safety representations in the vH instructed by the BLA.

Delaying extinction weakens the partial reinforcement extinction effect.

Conditioned responding that has been extinguished can spontaneously return when the conditioned stimulus (CS) is first presented after an extended delay. This spontaneous recovery of responding suggests that the memory of nonreinforced experience with the CS is impaired over the delay period. Rescorla (2007) provided evidence that this effect of time on nonreinforcement is not specific to extinction. He showed that a delay period can also reverse the reduction of responding established by a partial reinforcement schedule. Here we describe a series of experiments that attempted to confirm Rescorla's finding and additionally assessed the impact of the delay on another well-known consequence of partial reinforcement-the partial reinforcement extinction effect (PREE). Like Rescorla, we used a Pavlovian conditioning procedure with rats, measuring magazine activity during a CS that signaled food. Unlike Rescorla, we did not find that responding acquired under partial reinforcement spontaneously increased after a delay; however, we did observe a significant reduction in the PREE after that delay. We conclude that the passage of time has a selective effect on the retrieval of memories of nonreinforcement. Therefore, time produces spontaneous recovery by impairing retrieval of extinction memories but also weakens the PREE by impairing retrieval of memories of nonreinforcement that were acquired during partial reinforcement. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Dynamic tripartite construct of interregional engram circuits underlies forgetting of extinction memory.

Fear extinction allows for adaptive control of learned fear responses but often fails, resulting in a renewal or spontaneous recovery of the extinguished fear, i.e., forgetting of the extinction memory readily occurs. Using an activity-dependent neuronal labeling strategy, we demonstrate that engram neurons for fear extinction memory are dynamically positioned in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral hippocampus (vHPC), which constitute an engram construct in the term of directional engram synaptic connectivity from the BLA or vHPC to mPFC, but not that in the opposite direction, for retrieval of extinction memory. Fear renewal or spontaneous recovery switches the extinction engram construct from an accessible to inaccessible state, whereas additional extinction learning or optogenetic induction of long-term potentiation restores the directional engram connectivity and prevents the return of fear. Thus, the plasticity of engram construct underlies forgetting of extinction memory.

Effects of retrieval-extinction training on internet gaming disorder.

Background and aimsInternet gaming disorder (IGD) leads to serious impairments in cognitive functions, and lacks of effective treatments. Cue-induced craving is a hallmark feature of this disease and is associated with addictive memory elements. Memory retrieval-extinction manipulations could interfere with addictive memories and attenuate addictive syndromes, which might be a promising intervention for IGD. The aims of this study were to explore the effect of a memory retrieval-extinction manipulation on gaming cue-induced craving and reward processing in individuals with IGD.MethodsA total of 49 individuals (mean age: 20.52 ± 1.58) with IGD underwent a memory retrieval-extinction training (RET) with a 10-min interval (R-10min-E, n = 24) or a RET with a 6-h interval (R-6h-E, n = 25) for two consecutive days. We assessed cue-induced craving pre- and post-RET, and at the 1- and 3-month follow-ups. The neural activities during reward processing were also assessed pre- and post-RET.ResultsCompared with the R-6h-E group, gaming cravings in individuals with IGD were significantly reduced after R-10min-E training at the 3-month follow-up (P < 0.05). Moreover, neural activities in the individuals with IGD were also altered after R-10min-E training, which was corroborated by enhanced reward processing, such as faster responses (P < 0.05) and stronger frontoparietal functional connectivity to monetary reward cues, while the R-6h-E training had no effects.Discussion and ConclusionsThe two-day R-10min-E training reduced addicts’ craving for Internet games, restored monetary reward processing in IGD individuals, and maintained long-term efficacy.

The Effect of Extinction Cues on Response Recovery: A Meta-Analysis

A cue presented during Pavlovian extinction may help the recovery of the extinction memory, for which is called an extinction cue (EC). Pavlovian conditioning has been useful as a model of different behavior disorders and extinction as a model for their treatment. Extinguished responses may be recovered under different circumstances, akin to a relapse. Hence, it is important to strengthen extinction memory retrieval. There is contradictory evidence of the effectiveness of ECs to this end. There is also little information about the magnitude of response recovery prevention when using ECs. The magnitude of the ECs effect on response recovery was analyzed by a meta-analysis that considered possible sources of variance in the EC effect. The included studies were gathered mainly through scientific database search engines. Selection criteria included experiments that used a Pavlovian extinction and recovery procedure with an EC test. Effect size was calculated for each relevant experiment. Thirty-seven studies were included. These analyses showed that there is a robust effect of an extinction cue in reducing response recovery, d = 0.71, 95% CI [0.58, 0.85]. This effect is higher when a spontaneous recovery procedure is used and when the experiment is done with non-human animals. Interestingly, the type of control group did not affect the effect size. These results are robust under different statistical analyses, although a publication bias was detected.

Hippocampal Inputs in the Prelimbic Cortex Curb Fear after Extinction.

In contrast to easily formed fear memories, fear extinction requires prolonged training. The prelimbic cortex (PL), which integrates signals from brain structures involved in fear conditioning and extinction such as the ventral hippocampus (vHIP) and the basolateral amygdala (BL), is necessary for fear memory retrieval. Little is known, however, about how the vHIP and BL inputs to the PL regulate the display of fear after fear extinction. Using functional anatomy tracing in male rats, we found two distinct subpopulations of neurons in the PL activated by either the successful extinction or the relapse of fear. During the retrieval of fear extinction memory, the dominant input to active neurons in the PL was from the vHIP, whereas the retrieval of fear memory, regardless of the age of a memory and testing context, was associated with greater BL input. Optogenetic stimulation of the vHIP-PL pathway after one session of fear extinction increased conditioned fear, whereas stimulation of the vHIP inputs after several sessions of extinction decreased the conditioned fear response. This latter effect was, however, transient, as stimulation of this pathway 28 d after extinction increased conditioned fear response again. The results show that repeated fear extinction training gradually changes vHIP-PL connectivity, making fear suppression possible, whereas in the absence of fear suppression from the vHIP, signals from the BL can play a dominant role, resulting in high levels of fear.SIGNIFICANCE STATEMENT Behavioral therapies of fear are based on extinction learning. As extinction memories fade over time, such therapies produce only a temporary suppression of fear, which constitutes a clinical and societal challenge. In our study, we provide a framework for understating the underlying mechanism by which extinction of fear memories fade by demonstrating the existence of two subpopulations of neurons in the prelimbic cortex associated with low and high levels of fear. Insufficient extinction and exposure to the context in which fear memory was formed promoted high fear neuronal activity in the prelimbic cortex, leading to fear retrieval. Extensive extinction training, on the other hand, boosted low fear neuronal activity and, as a result, extinction memory retrieval. This effect was, however, transient and disappeared with time.

Adjunct pharmacotherapy for psychotherapy

AimsA variety of pharmacotherapies have been used to assist the psychotherapy process as “adjunctive therapies.” These drugs are used in an acute, targeted fashion, such that they are explicitly delivered in the context of psychotherapy for anxiety, mood and substance-dependence disorders (SUDs). Our narrative review highlights the potential of medically-assisted psychotherapy by outlining the current state of research on few of these medications and describing the basic science that supports their use.MethodFirstly, we researched an assortment of medications that have been used off-label to enhance psychotherapy, and selected a few that have received the most empirical attention in preclinical and clinical-trial settings. Our review of clinical trials focused on three of the most common psychiatric ailments. For all studies reviewed, we identify the strengths and weaknesses of the data supporting the use of the medications for the three aforementioned disorders.ResultD-cycloserine: accelerates the process of associative emotional learning, enhancing exposure therapy in the treatment of various anxiety disorders, including obsessive-compulsive disorder and posttraumatic stress disorder. Limited studies are available on efficacy in treating SUDs.Intranasal oxytocin: accelerates memory retrieval-extinction procedures used in posttraumatic stress disorder, and promotes prosocial cognition and behaviour, facilitating a therapeutic alliance. Sufficiently powered studies and safety studies are required before strong conclusions can be made.Propranolol: interrupts the reconsolidation of memories (leading to maladaptive learned responses) involved in posttraumatic stress disorder during memory-reactivation therapy sessions, but there is little evidence that this drug can be used for depression or SUDs.Psychedelics: may effect the brain's default mode network, engendering a transformative experience that is often followed by a reduction in psychiatric symptoms. 3,4-methylenedioxymethamphetamine may additionally modulate the amygdala response in a way that allows for reprocessing of traumatic memories, and improves the therapeutic alliance. Anxiety, mood, and SUDs appear to be positively influence by traditional and non-traditional (ketamine) psychedelics.ConclusionAlthough the efficacy of the medically-assisted psychotherapies reviewed is still under investigation, we propose that these novel treatment approaches may be preferred over traditional psychopharmacological treatments due to the presence of fewer chronic side effects, as well less toxicity and abuse potential. Furthermore, these adjunctive pharmacotherapies may help to reinforce the psychotherapeutic alliance and may ultimately yield better long-term treatment outcomes. If at least some of the adjunctive pharmacotherapies outlined in this review are found to be clinically efficacious and safe, patients will benefit from having more treatment options available to them in the future.

Effects of cortisol on retrieval of extinction memory in individuals with social anxiety

While exposure-based treatment for social anxiety disorder (SAD) has been shown to be effective, the high relapse rate remains a problem. Although relapse has been understood as the inability to retrieve extinction memory, the factors that influence the extent of retrieval of extinction memory have not been determined. This study aimed to examine whether the cortisol response to acute stressors in socially anxious individuals inhibits the retrieval of extinction memory, focusing on the cortisol response to acute stressors as a factor. Thirty-nine participants who scored 42 or more on the Liebowitz Social Anxiety Scale participated in the experiment for two consecutive days. On the first day, a fear conditioning task aimed at learning fear and extinction memory was administered, and on the second day, a psychosocial stress task (Trier Social Stress Test; TSST) was conducted, followed by an extinction retrieval test. The results indicated that cortisol responsiveness (Responder/Non-responder) was not associated with the retrieval of extinction memory indexed by subjective and physiological measures. However, a supplementary analysis revealed that the total amount of cortisol secretion was associated with attenuated retrieval of extinction memory. These findings suggest that the total cortisol secretions, rather than cortisol responsiveness to the acute stressor, may play a role in relapse.

Clinical implications of fear extinction in anxiety disorders

Abstract Anxiety disorders (ADs) are characterized by increased chronicity and comorbidity with other ADs. Although exposure is the most effective therapy option for ADs, some patients show poor treatment response and a heightened vulnerability for relapse after treatment completion. Hence, significant research effort needs to be devoted to improve the long-term effectiveness of exposure effects. Recent attempts to increase exposure therapy efficacy use strategies aimed at promoting the acquisition and retrieval of extinction memories. The present review illustrates the value and limitations of such extinction-based therapy approaches. We present and discuss recent findings from translational studies using cortisol and self-efficacy enhancement as an add-on to exposure therapy. We illustrate how the integration of findings from experimental research on fear extinction learning and self-efficacy could advance the development of more optimized treatments for ADs.

Hippocampal circuits underlie improvements in self-reported anxiety following mindfulness training.

IntroductionMindfulness meditation has successfully been applied to cultivate skills in self‐regulation of emotion, as it employs the unbiased present moment awareness of experience. This heightened attention to and awareness of sensory experience has been postulated to create an optimal therapeutic exposure condition and thereby improve extinction learning. We recently demonstrated increased connectivity in hippocampal circuits during the contextual retrieval of extinction memory following mindfulness training.MethodsHere, we examine the role of structural changes in hippocampal subfields following mindfulness training in a randomized controlled longitudinal study using a two‐day fear‐conditioning and extinction protocol.ResultsWe demonstrate an association between mindfulness training‐related increases in subiculum and decreased hippocampal connectivity to lateral occipital regions during contextual retrieval of extinguished fear. Further, we demonstrate an association between decreased connectivity and decreases in self‐reported anxiety following mindfulness training.ConclusionsThe results highlight the role of the subiculum in gating interactions with contextual stimuli during memory retrieval and, also, the mechanisms through which mindfulness training may foster resilience.

Memory Retrieval-Extinction Combined With Virtual Reality Reducing Drug Craving for Methamphetamine: Study Protocol for a Randomized Controlled Trial.

BackgroundRelapse, often precipitated by drug-associated cues that evoke craving, is a key problem in the treatment of methamphetamine use disorder (MUD). Drug-associated memories play a major role in the maintenance of relapse. Extinction training is a common method for decreasing drug craving by suppressing drug-associated memories. However, the effects are often not permanent, which is evident in form of spontaneous recovery or renewal of cue-elicited responses. Based on memory reconsolidation theory, the retrieval-extinction (R-E) paradigm may be more effective in decreasing spontaneous recovery or renewal responses than extinction. After the original memory reactivated to a labile state, extinction will be introduced within the reconsolidation window, thereby updating drug-associated memories. However, there are still some controversial results, which suggest that the reactivation of drug-associated memories and the 10 min-6 h of limited time window are two main elements in the R-E protocol. Virtual reality (VR) is supposed to promote memory reactivation by providing vivid drug-related stimuli when compared with movies.ObjectiveThe aim of this study is to examine the effectiveness of R-E training combined with VR on reducing spontaneous recovery or renewal of cue-elicited responses, in comparison to extinction, R-E training provided outside the time window of 6 h and R-E training retrieved using videos, in methamphetamine abusers.MethodsThe study is a parallel matched controlled study including 95 participants with MUD. Participants will be randomly assigned to either a R-10 min-E group (methamphetamine-related cues retrieval in VR followed by extinction after 10 min) or a NR-10 min-E group (neutral cues retrieval in VR followed by extinction after 10 min) or a R-6 h-E group (methamphetamine-related cues retrieval in VR followed by extinction after 6 h) or a RV-10 min-E group (methamphetamine-related cues retrieval in videos followed by extinction after 10 min). Cue-evoked craving and reactivity will be assessed at pre-test and at 1 day, 1 week, 1 month, and 6-month post-tests.DiscussionTo our knowledge, this study will probably be the first study to examine the efficacy of R-E training combined with VR to reduce cue-evoked responses in people with MUD. This innovative non-pharmacological intervention targeting drug-associated memories may provide significant clinical implications for reducing relapse, providing the study confirms its efficacy.Clinical Trial RegistrationThe trial is registered with Chinese Clinical Trial Registry at 17 October 2018, number: ChiCTR1800018899, URL: http://www.chictr.org.cn/showproj.aspx?proj=30854

Dynamic remodeling of a basolateral-to-central amygdala glutamatergic circuit across fear states.

Acquisition and extinction of learned fear responses utilize conserved but flexible neural circuits. Here we show that acquisition of conditioned freezing behavior is associated with dynamic remodeling of relative excitatory drive from the basolateral amygdala (BLA) away from corticotropin releasing factor-expressing (CRF+) central lateral amygdala (CeL) neurons, and toward non-CRF+ (CRF−) and somatostatin-expressing (SOM+) neurons, while fear extinction training remodels this circuit back toward favoring CRF+ neurons. Importantly, BLA activity is required for this experience-dependent remodeling, while directed inhibition of the BLA-CeL circuit impairs both fear memory acquisition and extinction memory retrieval. Additionally, ectopic excitation of CRF+ neurons impairs memory acquisition and facilities extinction, whereas CRF+ neuron inhibition impairs extinction memory retrieval, supporting the notion that CRF+ neurons serve to inhibit learned freezing behavior. These data suggest afferent-specific dynamic remodeling of relative excitatory drive to functionally distinct subcortical neuronal-output populations represent an important mechanism underlying experience-dependent modification of behavioral selection.

The role of hippocampal spatial representations in contextualization and generalization of fear

Using contextual information to predict aversive events is a critical ability that protects from generalizing fear responses to safe contexts. Animal models have demonstrated the importance of spatial context representations within the hippocampal formation in contextualization of fear learning. The ventromedial prefrontal cortex (vmPFC) is known to play an important role in safety learning, possibly also through the incorporation of context information. However, if contextual representations are related to context-dependent expression of fear memory in humans remains unclear. Twenty-one healthy participants underwent functional MRI combined with a cue-context conditioning paradigm within a self-navigated virtual reality environment. The environment included two buildings (Threat and Safe context), which had distinct features outside but were identical inside. Within each context, participants saw two cues (CS+, CS-). The CS+ was consistently (100% reinforcement rate) paired with an electric shock in the Threat context, but never in the Safe context. The CS- was never paired with a shock. We found robust differential skin conductance responses (SCRs; CS+ ​> ​CS-) in the Threat context, but also within the Safe context, indicating fear generalization. Within the Safe context, vmPFC responses to the CS+ were larger than those in the Threat context. We furthermore found environment-specific representations for the two contexts in the training paradigm (i.e., before conditioning took place) in the hippocampus to be related to fear expression and generalization. Namely, participants with a weak context representation (z-score < 1.65) showed stronger fear generalization compared to participants with a strong context representation (z-score > 1.65). Thus, a weak neural representation strength of spatial context may explain overgeneralization of memory to safe contexts. In addition, our findings demonstrate that context-dependent regulation of fear expression engages ventromedial prefrontal pathways suggesting this involves a similar mechanism that is known to be involved in retrieval of extinction memory.

Brain functional connectivity after cognitive-bias modification and behavioral changes in abstinent alcohol-use disorder patients

The use of the cognitive-bias modification (CBM) method has emerged as a therapeutic complement in the treatment of alcoholism, producing changes at behavioral and brain level. Nevertheless, the impact of the CBM procedure could be improved by the memory retrieval-extinction process (REP). Different studies have demonstrated that the retrieval of drug memories before extinction training later reduced the reinstatement of drug-seeking behavior. The main aim of this work was to study the effect of the CBM procedure itself, as well as in combination with the activation of alcohol-related memories, on the brain oscillatory activity of abstinent patients with alcohol-use disorder. The study sample comprised 33 patients divided into three groups: A-CBM (alcohol-related memory activation + CBM), N-CBM (neutral memory activation + CBM) and N-INT (no-intervention) groups. A resting-state EEG was obtained before and after each protocol, along with the assessment of the automatic action tendencies. A-CBM group showed a general alpha synchronization increase after the protocol, while the other groups did not show any significant change. Besides, A-CBM group showed significant intra and inter-group differences in the automatic action tendencies after the protocol, reflected in higher avoidance bias toward appetitive, aversive and without context alcohol-related stimuli. The alpha phase synchronization increase could be the neural manifestation of the conditioning produced between the alcohol-related stimuli and the automatic avoidance response. Moreover, the activation of the alcohol-related memories favors this conditioning with those alcohol-related stimuli associated with the activated memories, because it increases their threat level for the abstinence maintenance.

Methadone Induced Memory Retrieval-extinction Procedure in Heroin Addicts

Methadone Induced Memory Retrieval-extinction Procedure in Heroin Addicts

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

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]) 1hour before the extinction sessions decreased the heroin-priming-induced reinstatement, renewal, and spontaneous recovery of heroin seeking after 28days 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.