Reconsolidation Maintains Cocaine/Drug Memory Strength

Contextual drug-associated memories precipitate craving and relapse in cocaine users. Such associative memories can be weakened through interference with memory reconsolidation, a process by which memories are maintained following memory retrieval-induced destabilization. We hypothesized that cocaine-memory reconsolidation requires cannabinoid type 1 receptor (CB1R) signaling based on the fundamental role of the endocannabinoid system in synaptic plasticity and emotional memory processing. Using an instrumental model of cocaine relapse, we evaluated whether systemic CB1R antagonism (AM251; 3 mg/kg, i.p.) during memory reconsolidation altered (1) subsequent drug context-induced cocaine-seeking behavior as well as (2) cellular adaptations and (3) excitatory synaptic physiology in the basolateral amygdala (BLA) in male Sprague Dawley rats. Systemic CB1R antagonism, during, but not after, cocaine-memory reconsolidation reduced drug context-induced cocaine-seeking behavior 3 d, but not three weeks, later. CB1R antagonism also inhibited memory retrieval-associated increases in BLA zinc finger 268 (zif268) and activity regulated cytoskeletal-associated protein (Arc) immediate-early gene (IEG) expression and changes in BLA AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subunit phosphorylation that likely contribute to increased receptor membrane trafficking and synaptic plasticity during memory reconsolidation. Furthermore, CB1R antagonism increased memory reconsolidation-associated spontaneous EPSC (sEPSC) frequency in BLA principal neurons during memory reconsolidation. Together, these findings suggest that CB1R signaling modulates cellular and synaptic mechanisms in the BLA that may facilitate cocaine-memory strength by enhancing reconsolidation or synaptic reentry reinforcement, or by inhibiting extinction-memory consolidation. These findings identify the CB1R as a potential therapeutic target for relapse prevention. SIGNIFICANCE STATEMENT Drug relapse can be triggered by the retrieval of context-drug memories on re-exposure to a drug-associated environment. Context-drug associative memories become destabilized on retrieval and must be reconsolidated into long-term memory stores to persist. Hence, targeted interference with memory reconsolidation can weaken maladaptive context-drug memories and reduce the propensity for drug relapse. Our findings indicate that cannabinoid type 1 receptor (CB1R) signaling is critical for context-cocaine memory reconsolidation and subsequent drug context-induced reinstatement of cocaine-seeking behavior. Furthermore, cocaine-memory reconsolidation is associated with CB1R-dependent immediate-early gene (IEG) expression and changes in excitatory synaptic proteins and physiology in the basolateral amygdala (BLA). Together, our findings provide initial support for CB1R as a potential therapeutic target for relapse prevention.

Reconsolidation normally functions to update and maintain memories in the long-term. However, this process can be disrupted pharmacologically to weaken memories. Exploiting such experimental amnesia to disrupt the maladaptive reward memories underpinning addiction may provide a novel therapeutic avenue to prevent relapse. Here, we tested whether targeted disruption of the reconsolidation of instrumental (operant) lever pressing for cocaine resulted in protection against different forms of relapse in a rat self-administration model. We first confirmed that systemic injection of the non-competitive N-methyl–D-aspartate receptor (NMDAR) antagonist MK-801 did impair reconsolidation to reduce spontaneous instrumental drug-seeking memory at test. This deficit was not rescued by pharmacological induction of stress with the anxiogenic α2-noradrenergic receptor antagonist yohimbine. In contrast, cocaine-seeking was restored to control levels following priming with cocaine itself, or presentation of a cocaine-associated cue. These results suggest that while stress-induced relapse can be reduced by disruption of instrumental memory reconsolidation, the apparent sparing of the pavlovian cue-drug memory permitted other routes to relapse. Therefore, future reconsolidation-based therapeutic strategies for addictive drug-seeking may need to target both instrumental and pavlovian memories.

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Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory reconsolidation; however, it is not known whether these brain regions interact or independently control this phenomenon. To investigate this question, rats were trained to lever press for cocaine reinforcement in a distinct environmental context followed by extinction training in a different context. Rats were then briefly re-exposed to the cocaine-paired context to destabilize cocaine-related memories, or they were exposed to an unpaired context. Immediately thereafter, the rats received unilateral microinfusions of anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral (BLA/DH disconnection) or ipsilateral DH, or they received contralateral or ipsilateral microinfusions of vehicle. They then remained in their home cages overnight or for 21 d, followed by additional extinction training and a test of cocaine-seeking behavior (nonreinforced active lever responding). BLA/DH disconnection following re-exposure to the cocaine-paired context, but not the unpaired context, impaired subsequent drug context-induced cocaine-seeking behavior relative to vehicle or ipsilateral ANI + B/M treatment. Prolonged home cage stay elicited a time-dependent increase, or incubation, of drug-context-induced cocaine-seeking behavior, and BLA/DH disconnection inhibited this incubation effect despite some recovery of cocaine-seeking behavior. Thus, the BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories, thereby facilitating the ability of drug-paired contexts to trigger cocaine-seeking behavior and contributing to the incubation of cocaine-seeking behavior.

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The basolateral amygdala (BLA) is a critical brain region for cocaine-memory reconsolidation. Corticotropin-releasing factor receptor type 1 (CRFR1) is densely expressed in the BLA, and CRFR1 stimulation can activate intra-cellular signaling cascades that mediate memory reconsolidation. Hence, we tested the hypothesis that BLA CRFR1 stimulation is necessary and sufficient for cocaine-memory reconsolidation. Using an instrumental model of drug relapse, male and female Sprague-Dawley rats received cocaine self-administration training in a distinct environmental context over 10 days followed by extinction training in a different context over 7 days. Next, rats were re-exposed to the cocaine-paired context for 15 min to initiate cocaine-memory retrieval and destabilization. Immediately or 6 h after this session, the rats received bilateral vehicle, antalarmin (CRFR1 antagonist; 500 ng/hemisphere), or corticotropin-releasing factor (CRF; 0.2, 30 or 500 ng/hemisphere) infusions into the BLA. Resulting changes in drug context-induced cocaine seeking (index of context-cocaine memory strength) were assessed three days later. Female rats self-administered more cocaine infusions and exhibited more extinction responding than males. Intra-BLA antalarmin treatment immediately after memory retrieval (i.e., when cocaine memories were labile), but not 6 h later (i.e., after memory reconsolidation), attenuated drug context-induced cocaine seeking at test independent of sex, relative to vehicle. Conversely, intra-BLA CRF treatment increased this behavior selectively in females, in a U-shaped dose-dependent fashion. In control experiments, a high (behaviorally ineffective) dose of CRF treatment did not reduce BLA CRFR1 cell-surface expression in females. Thus, BLA CRFR1 signaling is necessary and sufficient, in a sex-dependent manner, for regulating cocaine-memory strength.

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Established memories can be destabilized, updated, and reconsolidated into long-term memory stores. Memory updating and reconsolidation can alter the strength of maladaptive contextual drug memories and consequently context-induced drug craving and relapse. The dorsolateral septum (dlS) is a GABAergic nucleus that receives dense direct input from the cornu ammonis 3 regions of the dorsal hippocampus, a brain region that is critical for the maintenance of contextual cocaine memories. Accordingly, we tested the hypothesis that neuronal activity in the dlS regulates the strength of cocaine-predictive contextual memories prior to reconsolidation. Male and female Sprague-Dawley rats received cocaine self-administration training followed by extinction training in two different environmental contexts. After the last extinction training session, the rats were placed back into the cocaine-predictive context to retrieve and destabilize their cocaine-related contextual memories. Immediately or six hours after memory retrieval, the rats received intra-dlS vehicle or baclofen/muscimol (B/M; GABAB/A agonists) infusions to inhibit neuronal activity during or after memory updating/reconsolidation, respectively. Resulting changes in cocaine and extinction memory strength were assessed based on the magnitude of unreinforced lever responding in the two contexts. Intra-dlS B/M infusion immediately after memory retrieval increased subsequent context-induced cocaine seeking behaviors in male rats, but not in female rats, whereas delayed B/M treatment had no effects in male rats. Together these findings suggest that the dlS is selectively engaged during memory updating/reconsolidation to reduce the strength of cocaine memories in males, possibly contributing to sex differences in the progression of cocaine use disorder.

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RATIONAL Cue-induced craving memories, linked to drug-seeking behaviors, require key molecular processes for memory reconsolidation. Lidocaine, a sodium channel blocker, inhibits NMDA receptor activation and suppresses nitric oxide and ERK production. These processes are required for memory re-consolidation; inhibiting them may reduce cue-related craving memories in cocaine dependent subjects. OBJECTIVES To assess the efficacy of lidocaine in decreasing cue-induced cocaine craving and cocaine use. METHODS Treatment-seeking cocaine-dependent participants (n = 33, 25 men) were recruited. Personalized craving and relaxation scripts were developed. Participants were then randomly assigned in a double-blind design to either receive intravenous lidocaine immediately following a cocaine craving script (lidocaine/craving), saline following a craving script (saline/craving), or lidocaine following a relaxation script (lidocaine/relax). One week following the infusion, cue-induced craving was assessed in the same paradigm without an infusion. Cocaine use and craving were assessed for 4 weeks following infusion. RESULTS The administration of lidocaine during craving induction (lidocaine/craving) did not decrease cue-induced craving during craving reactivation one week later or craving and cocaine use over the 4-week follow-up period compared to the saline/craving group. There were no significant differences in craving and cocaine use between the lidocaine/relax and saline/craving groups. CONCLUSION Lidocaine administered following craving induction did not decrease subsequent cue-induced craving or cocaine use. Blocking the reconsolidation of craving-related memories with pharmacological agents remains an important area of investigation.

Exposure to drug-related cues often disrupts abstinence from cocaine use by triggering memories of drug effects, leading to craving and possible relapse. One prospective method of treatment is weakening cocaine-associated memories via impairment of memory reconsolidation. Previous experiments have shown that systemic injection of the amnestic agent garcinol impairs the reconsolidation of cocaine-cue memories in a temporally constrained, cue-specific, and persistent manner. Here, we investigated garcinol’s effect on cocaine-cue memory reconsolidation when administered to the lateral nucleus of the amygdala (LA), as well as its epigenetic activity following systemic garcinol administration and also when given in conjunction with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor. Rats received 12 days of cocaine self-administration training during which time an active lever press resulted in an i.v. cocaine infusion that was concurrently paired with the presentation of a light/tone cue. After 8 days of lever extinction, rats received a memory reactivation session followed by a cue-induced reinstatement test. Intra-LA garcinol following memory reactivation significantly impaired reconsolidation only if the memory was reactivated. Additional studies revealed a significant reduction in histone H3 K27 acetylation and reduced expression of the immediate-early genes Arc and Egr-1 in the LA. When administered alone, TSA enhanced the reinstatement of a cocaine-cue memory, an effect that was prevented when garcinol was concurrently administered. These data indicate the LA is a key structure responsive to garcinol, suggest that one of garcinol’s mechanisms of action is through the reduction of memory-related gene expression in the LA, implicate changes in histone acetylation in memory reconsolidation, and support garcinol as a potential therapeutic tool for sustaining abstinence.

Environmental cues can elicit robust cocaine reward memories, contributing to relapse to cocaine abuse. Memories can be manipulated pharmacologically by interfering with reconsolidation after reactivation. Clonidine, an α2 noradrenergic receptor agonist, was tested for its ability to block reconsolidation of cocaine environmental-paired memory. Male Sprague-Dawley rats completed an 8-day cocaine place conditioning procedure to establish a cocaine place preference. Cocaine memory was reactivated by exposure to the cocaine-paired environment in a drug-free state, followed immediately by administration of clonidine (10 or 50 µg/kg) or vehicle. Cocaine place preference was retested 24 h and 1 week later. Clonidine significantly attenuated the previously established cocaine place preference when tested 1 or 7 days later. To investigate the generalizability of this effect to other drug classes, morphine conditioned place preference was tested. Clonidine administration after morphine memory reactivation did not significantly alter the expression of morphine place preference. These results suggest that clonidine can interfere with reconsolidation of cocaine memory and may be a useful approach to reduce relapse.

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Substance use disorder is conceptualized as a form of maladaptive learning, whereby drug-associated memories, elicited by the presence of stimuli related to drug contexts or cues, contribute to the persistent recurrence of craving and the reinstatement of drug-seeking behavior. Hence, use of pharmacology or non-pharmacology way to disrupt drug-related memory holds promise to prevent relapse. Several studies have shown that memories can be unstable and susceptible to modification during the retrieval reactivation phase, termed the "reconsolidation time window". In this study, we use the classical conditioned place preference (CPP) model to investigate the role of aversive counterconditioning on drug-related memories during reconsolidation. Specifically, we uncovered that reconditioning drug cues through counterconditioning with LiCl-induced aversive outcomes following drug memory retrieval reduces subsequent drug-seeking behavior. Notably, the recall of cocaine- or morphine-CPP was eliminated when LiCl-induced aversive counterconditioning was performed 10 min, but not 6 h (outside the reconsolidation time window) after cocaine or morphine memory retrieval. In addition, the effect of LiCl-induced aversive counterconditioning could last for about 14 days. These results suggest that aversive counterconditioning during the reconsolidation of cocaine or morphine memory can prevent the re-seeking of cocaine or morphine, presumably by updating or replacing cocaine or morphine memories with aversive information.

Background: As a modulator of dopaminergic system, trace amine-associated receptor 1 has been shown to play a critical role in regulating the rewarding properties of additive drugs. It has been demonstrated that activation of trace amine-associated receptor 1 decreased the abuse-related behaviors of cocaine in rats. However, the role of trace amine-associated receptor 1 in specific stages of cocaine reward memory is still unclear. Methods: Here, using a cocaine-induced conditioned place preference model, we tested the effects of a selective trace amine-associated receptor 1 agonist RO5166017 on the expression, reconsolidation, and extinction of cocaine reward memory. Results: We found that RO5166017 inhibited the expression but not retention of cocaine-induced conditioned place preference. RO5166017 had no effect on the reconsolidation of cocaine reward memory. Pretreatment with RO5166017 before extinction hindered the formation of extinction long-term memory. RO5166017 did not affect the movement during the conditioned place preference test, indicating the inhibitory effect of RO5166017 on the expression of cocaine-induced conditioned place preference was not caused by locomotion inhibition. Using a cocaine i.v. self-administration model, we found that the combined trace amine-associated receptor 1 partial agonist RO5263397 with extinction had no effect on the following cue- and drug-induced reinstatement of cocaine-seeking behavior. Repeated administration of the trace amine-associated receptor 1 agonist during extinction showed a continually inhibitory effect on the expression of cocaine reward memory both in cocaine-induced conditioned place preference and cocaine self-administration models. Conclusions: Taken together, these results indicate that activation of trace amine-associated receptor 1 specifically inhibited the expression of cocaine reward memory. The inhibitory effect of trace amine-associated receptor 1 agonists on cocaine reward memory suggests that trace amine-associated receptor 1 agonists could be a promising agent to prevent cocaine relapse.

Summary Background Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder. An unconditioned stimulus (US)-triggers a memory reconsolidation updating procedure (MRUP) that has been developed and demonstrated its effectiveness in decreasing relapse to cocaine and heroin in preclinical models. However, utilizations of abused drugs as the US to initiate MRUP can be problematic. We therefore designed a translational rat study and human study to evaluate the efficacy of a novel methadone-initiated MRUP. Methods In the rodent study, male rats underwent heroin self-administration training for 10 consecutive days, and were randomly assigned to receive saline or methadone at 10 min, 1 h or 6 h before extinction training after 28-day withdrawal. The primary outcome was operant heroin seeking after reinstatement. In the human experimental study, male OUD patients were randomly assigned to get MRUP at 10 min or 6 h after methadone or methadone alone. The primary outcomes included experimental cue-induced heroin craving change, sustained abstinence and retention in the study at post intervention and the 5 monthly follow-up assessments. The secondary outcomes were changes in physiological responses including experimental cue-induced blood pressure and heart rate. Findings Methadone exposure but not saline exposure at 10 min or 1 h before extinction decreased heroin-induced reinstatement of heroin seeking after 28-day of withdrawal in rats (F (8,80) = 8.26, p < 0.001). In the human study, when the MRUP was performed 10 min, but not 6 h after methadone dosing, the MRUP promoted sustained abstinence from heroin throughout 5 monthly follow-up assessments compared to giving methadone alone without MRUP (Hazard Ratio [95%CI] of 0.43 [0.22, 0.83], p = 0.01). The MRUP at 10 min, but not at 6 h after dosing also decreased experimental cue-induced heroin craving and blood pressure increases during the 6-month study duration (group × months × cue types, F (12, 63·3) = 2.41, p = 0.01). Interpretation The approach of MRUP within about 1 to 6 h after a methadone dose potently improved several key outcomes of OUD patients during methadone maintenance treatment, and could be a potentially novel treatment to prevent opioid relapse. Funding National Natural Science Foundation of China (NO. U1802283, 81761128036, 82001400, 82001404 and 31671143) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology (NO. 2021ZD0200800)

Previously consolidated memories have the potential to enter a state of lability upon memory recall, during which time the memory can be altered before undergoing an additional consolidation-like process and being stored again as a long-term memory. Blocking reconsolidation of aberrant memories has been proposed as a potential treatment for psychiatric disorders including addiction. Here we investigated of the effect of systemically administering the protein synthesis inhibitor cycloheximide or the β-adrenergic antagonist propranolol on reconsolidation. Rats were trained to self-administer cocaine, during which each lever press resulted in the presentation of a cue paired with an intravenous infusion of cocaine. After undergoing lever press extinction to reduce operant responding, the cue memory was reactivated and rats were administered systemic injections of propranolol, cycloheximide, or vehicle. Post-reactivation cycloheximide, but not propranolol, resulted in a reactivation-dependent decrease in cue-induced reinstatement, indicative of reconsolidation blockade by protein synthesis inhibition. The present data indicate that systemically targeting protein synthesis as opposed to the β-adrenergic system may more effectively attenuate the reconsolidation of a drug-related memory and decrease drug-seeking behavior.

This research adds to the growing body of evidence that instrumental memories (memories of interactions with the world) undergo reconsolidation, a class of memory previously not thought to undergo reconsolidation. Furthermore, we suggest that there may be a role for coactivation of accumbal D1Rs and NMDARs in the destabilization and reconsolidation of appetitive memory. Abstract Stored memories are dynamic and, when reactivated, can undergo a process of destabilization and reconsolidation to update them with new information. Reconsolidation has been shown for a variety of experimental settings; most recently for well-learned instrumental memories, a class of memory previously thought not to undergo reconsolidation. Here we tested, in rats, whether a weakly-trained lever-pressing memory destabilized following a shift in reinforcement contingency. We show that lever-pressing memory for both sucrose and cocaine reinforcement destabilized under appropriate conditions, and that the reconsolidation of this memory was impaired by systemic administration of the NMDA receptor (NMDAR) antagonist [5R,10S]-[+]-5-methyl-10,1-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801). We went on to investigate the potential role of the nucleus accumbens (NAc) in the reconsolidation of sucrose-reinforced instrumental memories, showing that co-infusion of the NMDAR antagonist 2-amino-5-phosphonopentanoic acid (AP-5) and the dopamine-1 receptor (D1R) antagonist 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol (SCH23390) into the NAc prior to memory reactivation impaired reconsolidation; however, there was no effect when these drugs were infused alone. Further investigation of this effect suggests the combined infusion disrupted the reconsolidation of pavlovian components of memory, and we hypothesize that coactivation of accumbal D1Rs and NMDARs may contribute to both the destabilization and reconsolidation of appetitive memory. Our work demonstrates that weakly-trained instrumental memories undergo reconsolidation under similar parameters to well-trained ones, and also suggests that receptor coactivation in the NAc may contribute to memory destabilization. Furthermore, it provides an important demonstration of the therapeutic potential of reconsolidation-based treatments that target the instrumental components of memory in maladaptive drug seeking.

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Pyramidal neurons in the medial prefrontal cortex (mPFC) critically contribute to cocaine-seeking behavior in humans and rodents. Activity of these neurons is significantly modulated by GABAergic, parvalbumin-containing, fast-spiking interneurons, the majority of which are enveloped by specialized structures of extracellular matrix called perineuronal nets (PNNs), which are integral to the maintenance of many types of plasticity. Using a conditioned place preference (CPP) procedure, we found that removal of PNNs primarily from the prelimbic region of the mPFC of adult, male, Sprague Dawley rats impaired the acquisition and reconsolidation of a cocaine-induced CPP memory. This impairment was accompanied by a decrease in the number of c-Fos-positive cells surrounded by PNNs. Following removal of PNNs, the frequency of inhibitory currents in mPFC pyramidal neurons was decreased; but following cocaine-induced CPP, both frequency and amplitude of inhibitory currents were decreased. Our findings suggest that cocaine-induced plasticity is impaired by removal of prelimbic mPFC PNNs and that PNNs may be a therapeutic target for disruption of cocaine CPP memories.

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The intracellular mechanisms underlying memory reconsolidation critically involve cAMP signaling. These events were originally attributed to PKA activation by cAMP, but the identification of Exchange Protein Activated by cAMP (Epac), as a distinct mediator of cAMP signaling, suggests that cAMP-regulated processes that subserve memory reconsolidation are more complex. Here we investigated how activation of Epac with 8-pCPT-cAMP (8-CPT) impacts reconsolidation of a memory that had been associated with cocaine self-administration. Rats were trained to lever press for cocaine on an FR-1 schedule, in which each cocaine delivery was paired with a tone+light cue. Lever pressing was then extinguished in the absence of cue presentations and cocaine delivery. Following the last day of extinction, rats were put in a novel context, in which the conditioned cue was presented to reactivate the cocaine-associated memory. Immediate bilateral infusions of 8-CPT into the basolateral amygdala (BLA) following reactivation disrupted subsequent cue-induced reinstatement in a dose-dependent manner, and modestly reduced responding for conditioned reinforcement. When 8-CPT infusions were delayed for 3 hours after the cue reactivation session or were given after a cue extinction session, no effect on cue-induced reinstatement was observed. Co-administration of 8-CPT and the PKA activator 6-Bnz-cAMP (10 nmol/side) rescued memory reconsolidation while 6-Bnz alone had no effect, suggesting an antagonizing interaction between the two cAMP signaling substrates. Taken together, these studies suggest that activation of Epac represents a parallel cAMP-dependent pathway that can inhibit reconsolidation of cocaine-cue memories and reduce the ability of the cue to produce reinstatement of cocaine-seeking behavior.

Persistent traces of drug reward memories contribute to intense craving and often trigger relapse. A number of pharmacological interventions on drug-associated memories have shown significant benefits in relapse prevention at a preclinical level but their translational potential is limited due to deleterious side effects. Propranolol, a non-specific β-adrenergic receptors antagonist, is known for its ability to erase maladaptive memories associated with nicotine or cocaine in rodents and humans. However, little is known about its effect on reconsolidation of heroin memory and heroin seeking. In the present study, rats with a history of intravenous heroin self-administration received the propranolol treatment (10 mg/kg; i.p.) at different time windows with or without CS (conditioned stimulus) exposure. Our results showed that propranolol, when administered immediately after CS exposure but not 6 h later, can significantly attenuate cue-induced and drug-primed reinstatement of heroin seeking, suggesting that propranolol has the ability to disrupt heroin memory and reduce relapse. The propranolol treatment without retrieval of drug memory had no effect on subsequent reinstatement of heroin seeking, suggesting that its interfering effects are retrieval-dependent. Importantly, the effects of propranolol were long lasting as rats showed diminished drug seeking even 28 days after the treatment. Altogether, our study suggests that propranolol can interfere with reconsolidation of heroin memory and reduce subsequent drug seeking, making it an attractive therapeutic candidate for the treatment of opioid addiction and relapse prevention.

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Abstract Background Drug memories become labile and reconsolidated after retrieval by presentation of environmental cues (conditioned stimulus) or drugs (unconditioned stimulus). Whether conditioned stimulus and unconditioned stimulus retrieval trigger different memory reconsolidation processes is not clear. Methods Protein synthesis inhibitor or β-adrenergic receptor (β-AR) antagonist was systemically administrated or intra-central amygdala infused immediately after cocaine reexposure in cocaine-conditioned place preference or self-administration mice models. β-ARs were selectively knocked out in the central amygdala to further confirm the role of β-adrenergic receptor in cocaine reexposure-induced memory reconsolidation of cocaine-conditioned place preference. Results Cocaine reexposure triggered de novo protein synthesis dependent memory reconsolidation of cocaine-conditioned place preference. Cocaine-priming-induced reinstatement was also impaired with post cocaine retrieval manipulation, in contrast to the relapse behavior with post context retrieval manipulation. Cocaine retrieval, but not context retrieval, induced central amygdala activation. Protein synthesis inhibitor or β1-adrenergic receptor antagonist infused in the central amygdala after cocaine retrieval, but not context retrieval, inhibited memory reconsolidation and reinstatement. β1-adrenergic receptor knockout in the central amygdala suppressed cocaine retrieval-triggered memory reconsolidation and reinstatement of cocaine conditioned place preference. β1-adrenergic receptor antagonism after cocaine retrieval also impaired reconsolidation and reinstatement of cocaine self-administration. Conclusions Cocaine reward memory triggered by unconditioned stimulus retrieval is distinct from conditioned stimulus retrieval. Unconditioned stimulus retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the central amygdala. Post unconditioned stimulus retrieval manipulation can prevent drug memory reconsolidation and relapse to cocaine, thus providing a potential strategy for the prevention of substance addiction. Significance Statement It is well known that drug memories become labile and reconsolidated upon retrieval by the presentation of conditioned stimulus (CS) or unconditioned stimulus (US). Whether CS and US retrieval trigger different memory reconsolidation processes is unknown. In this study, we found that US retrieval, but not CS retrieval, triggered memory reconsolidation of cocaine-conditioned place preference dependent on β1-AR and de novo protein synthesis in the central amygdala. Furthermore, cocaine priming-induced reinstatement was impaired with post US retrieval manipulation in contrast to the relapse behavior with post CS retrieval manipulation. In cocaine self-administration, β1-AR antagonism after US retrieval also impaired reconsolidation and reinstatement. Our study indicates that reconsolidation of cocaine reward memory triggered by US retrieval is distinct from CS retrieval. US retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the central amygdala.

As a noninvasive behavioral intervention, the retrieval-extinction (R-E) procedure has drawn much research attention for its capacity to target the reconsolidation of maladaptive memories. However, later research findings suggest that the cause and consequence of R-E may be more complicated than previously suggested. For example, the R-E procedure could increase an animal's motivation for drug-seeking under certain circumstances, and the reversed extinction-retrieval (E-R) procedure could also suppress the drug memory. Two possible mechanisms underlying the R-E procedure have been proposed: the reconsolidation-update and extinction-facilitation hypotheses. To elucidate the paradoxical prior findings and examine these two hypotheses, we systematically examined the efficacy of the extinction (E), R-E, and E-R procedures in mice's low-dose versus high-dose cocaine-induced conditioned place preference (CPP) memory. We showed that the dose of cocaine is a crucial determinant of the efficacy of the three behavioral interventions. The E procedure exerted a long-lasting suppression of the low-dose cocaine CPP memory, while the R-E procedure induced more memory defects than the E and E-R procedures in its long-term suppression of the high-dose cocaine CPP memory. It warrants further investigation of whether the R-E procedure's underlying neurochemical and molecular mechanisms differ from the E and E-R procedures.

Glutamatergic synapses are key cellular sites where cocaine experience creates memory traces that subsequently promote cocaine craving and seeking. In addition to making across-the-board synaptic adaptations, cocaine experience also generates a discrete population of new synapses that selectively encode cocaine memories. These new synapses are glutamatergic synapses that lack functionally stable AMPARs, often referred to as AMPAR-silent synapses or, simply, silent synapses. They are generated de novo in the NAc by cocaine experience. After drug withdrawal, some of these synapses mature by recruiting AMPARs, contributing to the consolidation of cocaine-associated memory. After cue-induced retrieval of cocaine memories, matured silent synapses alternate between two dynamic states (AMPAR-absent vs AMPAR-containing) that correspond with the behavioral manifestations of destabilization and reconsolidation of these memories. Here, we review the molecular mechanisms underlying silent synapse dynamics during behavior, discuss their contributions to circuit remodeling, and analyze their role in cocaine-memory-driven behaviors. We also propose several mechanisms through which silent synapses can form neuronal ensembles as well as cross-region circuit engrams for cocaine-specific behaviors. These perspectives lead to our hypothesis that cocaine-generated silent synapses stand as a distinct set of synaptic substrates encoding key aspects of cocaine memory that drive cocaine relapse.

Drug use is provoked by the presentation of drug-associated cues, even following long periods of abstinence. Disruption of these learned associations would therefore limit relapse susceptibility. Drug-associated memories are susceptible to long-term disruption during retrieval and shortly after, during memory reconsolidation. Recent evidence reveals that retrieval and reconsolidation are dependent on β-adrenergic receptor (β-AR) activation. Despite this, whether retrieval and reconsolidation are dependent on identical or distinct neural mechanisms is unknown. The prelimbic medial prefrontal cortex (PL-mPFC) and basolateral amygdala (BLA) have been implicated in the expression and reconsolidation of associative memories. Therefore, we investigated the necessity of β-AR activation within the PL-mPFC and BLA for cocaine-associated memory retrieval and reconsolidation in rats. Before or immediately after a cocaine-induced conditioned place preference (CPP) retrieval trial, β-AR antagonists were infused into the PL-mPFC or BLA, followed by daily testing. PL-mPFC infusions before, but not after, a CPP trial disrupted CPP memory retrieval and induced a persistent deficit in retrieval during subsequent trials. In contrast, BLA β-AR blockade had no effect on initial CPP memory retrieval, but prevented CPP expression during subsequent trials indicative of reconsolidation disruption. Our results reveal a distinct dissociation between the neural mechanisms required for cocaine-associated memory retrieval and reconsolidation. Using patch-clamp electrophysiology, we also show that application of a β-AR antagonist prevents norepinephrine-induced potentiation of PL-mPFC pyramidal cell and γ-aminobutyric-acid (GABA) interneuron excitability. Thus, targeted β-AR blockade could induce long-term deficits in drug-associated memory retrieval by reducing neuronal excitability, providing a novel method of preventing cue-elicited drug seeking and relapse.

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RATIONALE Cocaine addiction is a global health problem with no approved pharmacotherapies. Preclinical research indicates the non-intoxicating phytocannabinoid, cannabidiol (CBD), can reduce addiction-relevant behaviour for several drug classes (e.g. ethanol, opiates, psychostimulants) in rodents. However, research into the effects of CBD on cocaine addiction-like behaviours is limited, and the acute effects of CBD on cocaine reward are unknown. OBJECTIVES The present experiments sought to clarify the effects of CBD (10 mg/kg) on the acquisition, consolidation, reconsolidation, extinction and drug-primed reinstatement of cocaine (15 mg/kg) conditioned place preference (CPP) in adult male C57BL6/J mice. METHODS In five separate experiments, CBD was administered 1) prior to cocaine-context pairings, to target acquisition of cocaine-context memory; 2) immediately after cocaine-context pairings, to target consolidation of cocaine-context memory; 3) after a brief reactivation session, to target reconsolidation of cocaine memory; 4) prior to extinction sessions; and 5) prior to cocaine-primed reinstatement. RESULTS CBD treatment reduced preference for the cocaine-context 20 days after CBD cessation. CBD also reduced consolidation of cocaine memory, and this was evident 1 day after cessation of CBD treatment. Interestingly, CBD treatment also modified cocaine-induced locomotion. CBD did not affect reconsolidation of cocaine-induced place preference, the rate of extinction of cocaine memory, or drug-primed reinstatement of cocaine CPP. CONCLUSIONS These findings indicate specific effects of acute 10 mg/kg CBD on cocaine memory processes, suggesting delayed effects on cocaine preference and consolidation of cocaine memory, and support the therapeutic utility of CBD for targeting some drug-associated memory processes.

Methamphetamine abuse has become a serious public health problem. However, effective treatment for methamphetamine addiction remains elusive, especially considering its high rate of relapse after treatment. A conditioned stimulus (CS) memory retrieval–extinction procedure has been demonstrated to decrease reinstatement of cocaine, heroin, and alcohol seeking in rats, and to reduce cue-induced cravings in heroin and nicotine addicts. The goal of the present study is to explore the effect of the CS memory retrieval–extinction procedure on methamphetamine seeking in rats and the underlying mechanisms. We found that daily retrieval of methamphetamine-associated memories 1 h before extinction sessions decreased subsequent drug priming-induced reinstatement, spontaneous recovery, and renewal of methamphetamine seeking. We also found that retrieval of methamphetamine-associated memories induced neuronal activation in the basolateral amygdala (BLA), while presenting extinction within the time window of reconsolidation abolished the neuronal activation in BLA. These results indicate that the CS memory retrieval–extinction procedure could prevent reconsolidation of methamphetamine memory traces in BLA and subsequent methamphetamine craving and relapse.

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Exposure to drug-paired cues causes drug memories to be in a destabilized state and interfering with memory reconsolidation can inhibit relapse. Calpain, a calcium-dependent neutral cysteine protease, is involved in synaptic plasticity and the formation of long-term fear memory. However, the role of calpain in the reconsolidation of drug reward memory is still unknown. In the present study, using a conditioned place preference (CPP) model, we found that exposure to drug-paired contextual stimuli induced the activation of calpain and decreased the expression of glutamate receptor interacting protein 1 (GRIP1) in the nucleus accumbens (NAc) core, but not shell, of male rats. Infusions of calpain inhibitors in the NAc core immediately after retrieval disrupted the reconsolidation of cocaine/morphine cue memory and blocked retrieval-induced calpain activation and GRIP1 degradation. The suppressive effect of calpain inhibitors on the expression of drug-induced CPP lasted for at least 14 d. The inhibition of calpain without retrieval 6 h after retrieval or after exposure to an unpaired context had no effects on the expression of reward memory. Calpain inhibition after retrieval also decreased cocaine seeking in a self-administration model and this effect did not recover spontaneously after 28 d. Moreover, the knock-down of GRIP1 expression in the NAc core by lentivirus-mediated short-hairpin RNA blocked disruption of the reconsolidation of drug cue memories that was induced by calpain inhibitor treatment. These results suggest that calpain activity in the NAc core is crucial for the reconsolidation of drug reward memory via the regulation of GRIP1 expression. SIGNIFICANCE STATEMENT Calpain plays an important role in synaptic plasticity and long-term memory consolidation, however, its role in the reconsolidation of drug cue memory remains unknown. Using conditioned place preference and self-administration procedures, we found that exposure to drug-paired cues induced the activation of calpain and decreased glutamate receptor interacting protein 1 (GRIP1) expression in the nucleus accumbens (NAc) core. The inhibition of calpain activity in the NAc core immediately after retrieval disrupted the reconsolidation of cocaine/morphine cue memory that was blocked by prior GRIP1 knock-down. Our findings indicate that calpain-GRIP signaling is essential for the restabilization process that is associated with drug cue memory and the inhibition of calpain activity may be a novel strategy for the prevention of drug relapse.

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Alcohol addiction is a problem of great societal concern, for which there is scope to improve current treatments. One potential new treatment for alcohol addiction is based on disrupting the reconsolidation of the maladaptive Pavlovian memories that can precipitate relapse to drug-seeking behavior. In alcohol self-administering rats, we investigated the effects of bidirectionally modulating adrenergic signaling on the strength of a Pavlovian cue-alcohol memory, using a behavioral procedure that isolates the specific contribution of one maladaptive Pavlovian memory to relapse, the acquisition of a new alcohol-seeking response for an alcohol-associated conditioned reinforcer. The β-adrenergic receptor antagonist propranolol, administered in conjunction with memory reactivation, persistently disrupted the memory that underlies the capacity of a previously alcohol-associated cue to act as a conditioned reinforcer. By contrast, enhancement of adrenergic signaling by administration of the adrenergic prodrug dipivefrin at reactivation increased the strength of the cue-alcohol memory and potentiated alcohol seeking. These data demonstrate the importance of adrenergic signaling in alcohol-associated memory reconsolidation, and suggest a pharmacological target for treatments aiming to prevent relapse through the disruption of maladaptive memories.

Addicted individuals are highly susceptible to relapse when exposed to drug-associated conditioned stimuli (CSs; “drug cues”) even after extensive periods of abstinence. Until recently, these maladaptive emotional drug memories were believed to be permanent and resistant to change. The rediscovery of the phenomenon of memory reconsolidation—by which retrieval of the memory can, under certain conditions, destabilize the previously stable memory before it restabilizes in its new, updated form—has led to the hypothesis that it may be possible to disrupt the strong maladaptive drug-memories that trigger a relapse. Furthermore, recent work has suggested that extinction training “within the reconsolidation window” may lead to a long-term reduction in relapse without the requirement for pharmacological amnestic agents. However, this so-called “retrieval-extinction” effect has been inconsistently observed in the literature, leading some to speculate that rather than reflecting memory updating, it may be the product of facilitation of extinction. In this mini review article, we will focus on factors that might be responsible for the retrieval-extinction effects on preventing drug-seeking relapse and how inter-individual differences may influence this therapeutically promising effect. A better understanding of the psychological and neurobiological mechanisms underpinning the “retrieval-extinction” paradigm, and individual differences in boundary conditions, should provide insights with the potential to optimize the translation of “retrieval-extinction” to clinical populations.

Memories associated with substance use disorders, or substance-associated cues increase the likelihood of craving and relapse during abstinence. There is a growing consensus that manipulation of synaptic plasticity may reduce the strength of substance abuse-related memories. On the biological front, there are new insights that suggest memories associated with substance use disorder may follow unique neurobiological pathways that render them more accessible to pharmacological intervention. In parallel to this, research in neurochemistry has identified several potential candidate molecules that could influence the formation and maintenance of long-term memory. Drugs that target these molecules (blebbistatin, isradipine and zeta inhibitory peptide) have shown promise at the preclinical stage. In this review, we shall provide an overview of the evolving understanding on the biochemical mechanisms involved in memory formation and expound on the premise that substance use disorder is a learning disorder.

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Mice subjected to morphine locomotor sensitization develop increased anxiety-behavior expression during protracted morphine withdrawal. This behavioral change is dependent on reexposure to the context of locomotor sensitization and reflects a state of conditioned anxiety. In this study, the effect of memory reconsolidation on the expression of conditioned anxiety in mice with protracted morphine withdrawal was examined. Five experimental protocols involving male C57BL/6 mice were used in which the animals were subjected to locomotor sensitization induced by morphine and reexposed to the context associated with the drug effect 28 days after locomotor sensitization and immediately after subjected to elevated plus maze. In experiment 1, mice were subjected or not to memory reactivation session and was observed that memory reactivation 27 days after sensitization reduced conditioned anxiety. In experiment 2, mice were subjected to memory reactivation, 24hours, 6hours or 1hour before contextual reexposure, and the effect of memory reactivation coincided with the temporal requirement for reconsolidation. In experiment 3, which involved exposure to a situation of acute stress immediately before memory reactivation, the mice demonstrated a return to increased conditioned anxiety. To confirm the influence of reconsolidation, in experiments 4 and 5, mice subjected to memory reactivation were treated with Nimodipine, diazepam or cyclohexamine, substances commonly used as pharmacological controls in reconsolidation experiments. Treatment with each substance separately inhibited the effect of reactivation in experiment 5 (presence of acute stressor) but not in experiment 4 (absence of acute stressor). These results suggest that, in our experimental model, reconsolidation is mediated through updating of the emotional valence of contextual memory associated with the administration of morphine.

RationalePreclinical reconsolidation research offers the first realistic opportunity to pharmacologically weaken the maladaptive memory structures that support relapse in drug addicts. N-methyl D-aspartate receptor (NMDAR) antagonism is a highly effective means of blocking drug memory reconsolidation. However, no research using this approach exists in human addicts.ObjectivesThe objective of this study was to assess the potential and clinical outcomes of blocking the reconsolidation of cue-smoking memories with memantine in quitting smokers.MethodsFifty-nine dependent and motivated to quit smokers were randomised to one of three groups receiving the following: (1) memantine with or (2) without reactivation of associative cue-smoking memories or (3) reactivation with placebo on their target quit day in a double-blind manner. Participants aimed to abstain from smoking for as long as possible. Levels of smoking and FTND score were assessed prior to intervention and up to a year later. Primary outcome was latency to relapse. Subjective craving measures and attentional bias to smoking cues were assessed in-lab.ResultsAll study groups successfully reduced their smoking up to 3 months. Memantine in combination with smoking memory reactivation did not affect any measure of smoking outcome, reactivity or attention capture to smoking cues.ConclusionsBrief exposure to smoking cues with memantine did not appear to weaken these memory traces. These findings could be due to insufficient reconsolidation blockade by memantine or failure of exposure to smoking stimuli to destabilise smoking memories. Research assessing the treatment potential of reconsolidation blockade in human addicts should focus on identification of tolerable drugs that reliably block reward memory reconsolidation and retrieval procedures that reliably destabilise strongly trained memories.

Methamphetamine (METH) is a highly addictive psychostimulant drug. A key behavior of addiction is the relapse to drug-seeking and self-administration after abstinence. Like small amounts of a drug, does sleep deprivation increase the risk of relapse. Thus, identifying the mechanisms of relapse, and inhibiting them, is one strategy to develop a better treatment of addiction. In this study, adolescent and adult male rats underwent a 7-day episode of REM sleep deprivation (RSD). Following this, they were trained to establish a METH (2 mg/kg, i.p.)-induced conditioned place preference (CPP). After CPP extinction, rats received a memory reactivation session to trigger METH-CPP reinstatement. Immediately after this session, they received the GABAB receptor (GABAB-R) agonist baclofen (0, 2.5, or 5 mg/kg, i.p.). The results showed that baclofen, administered during the reconsolidation phase of METH CPP, significantly reduced METH reinstatement in both adolescent and adult rats in a dose-dependent manner. In adolescent rats, RSD enhanced METH reward memory, while it had no effect on adult rats. Although baclofen consistently reduced METH reinstatement in RSD adolescent rats, this effect was not observed in RSD adult rats. Furthermore, RSD increased GABAB-R1 subunit expression in the prefrontal cortex of both age groups. However, baclofen did not affect GABAB-R1 subunit expression in either group. These findings provide evidence for a role of the GABAB-R in METH memory reconsolidation across different ages, its vulnerability to RSD. They further support the potential of baclofen as a treatment for mitigating behaviors associated with METH abuse.

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The amygdala has long been considered a primary locus in mediating the effects of previously drug-associated stimuli on subsequent drug-seeking behavior, and the NMDA subtype of glutamate receptor within the amygdala is important for the consolidation of associations between environmental conditioned stimuli and the effects of addictive drugs. Here we demonstrate that amygdala NMDA receptors are also necessary for the reconsolidation of drug-associated memories. Using a behavioral task that specifically measures the conditioned reinforcing properties of a previously drug-paired stimulus, we show that infusion of the NMDA receptor antagonist d(-)-2-amino-5-phosphonopentanoic acid (d-APV) into the basolateral amygdala before a memory reactivation session disrupted the drug-associated memory and abolished subsequent instrumental responding for conditioned reinforcement. This effect was memory reactivation dependent, and the memory deficit persisted for at least 4 weeks. In contrast, infusion of d-APV immediately after the memory reactivation session had no effect on subsequent responding for conditioned reinforcement, indicating that NMDA receptors have a temporally limited role in the reconsolidation process. Furthermore, in molecular studies, we show that the reconsolidation-impairing effect of d-APV is correlated with downstream reductions in expression of the plasticity-related immediate early gene, zif268. We also demonstrate that systemic antagonism of NMDA receptors with MK-801 [(+)-5-methyl-10,11-dihydro-SH-dibenzo[a,d]cyclohepten-5,10-imine maleate] before memory reactivation subsequently reduced previously acquired instrumental drug-seeking behavior that depends on drug-associated cues acting as conditioned reinforcers. These data suggest that drugs modulating glutamatergic transmission at the NMDA receptor may be useful in the future treatment of relapse prevention in drug addiction through memory reconsolidation blockade.

We have investigated the neurochemical mechanisms of memory reconsolidation and, in particular, the functional requirement for intracellular mechanisms initiated by beta-adrenergic signaling. We show that propranolol, given in conjunction with a memory reactivation session, can specifically disrupt the conditioned reinforcing properties of a previously appetitively reinforced conditioned stimulus (CS), whether the stimulus had been associated with self-administered cocaine or with sucrose. These data show that memories for both drug and nondrug CS-US associations are dependent on beta-adrenergic receptor-mediated signaling for their reconsolidation, with implications for the potential development of a novel treatment for drug addiction and some forms of obesity.

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Compulsive drug-seeking behavior and its renewal in former drug addicts is promoted by several situations, among which reactivation of drug withdrawal memories plays a crucial role. A neural hypothesis is that such memories reactivate the circuits involved in withdrawal itself and promote a motivational state leading to drug seeking or taking. To test this hypothesis, we have analyzed the neural circuits and cell populations recruited when opiate-dependent rats are reexposed to stimuli previously paired with withdrawal (memory retrieval) and compared them with those underlying acute withdrawal during conditioning (memory formation). Using in situ hybridization for c-fos expression, we report here that reexposure to a withdrawal-paired environment induced conditioned c-fos responses in a specific limbic circuit, which can be partially dissociated from the structures involved in acute withdrawal. At the amygdala level, c-fos responses were doubly dissociated between the central and basolateral (BLA) nuclei, when comparing the two situations. Detailed phenotypical analyses in the amygdala and ventral tegmental area (VTA) show that specific subpopulations in the BLA are differentially involved in the formation and retrieval of withdrawal memories, and strikingly that a population of VTA dopamine neurons is activated in both situations. Together, this indicates that withdrawal memories can drive activity changes in specific neuronal populations of interconnected limbic areas known to be involved in aversive motivational processes. This first study on the neural substrates of withdrawal memories strongly supports an incentive-motivational view of withdrawal in opiate addiction that could be crucial in compulsive drug seeking and relapse.

Affective memories associated with the negative emotional state experienced during opiate withdrawal are central in maintaining drug taking, seeking, and relapse. Nucleus accumbens (NAC) is a key structure for both acute withdrawal and withdrawal memories reactivation, but the NAC neuron coding properties underpinning the expression of these memories remain largely unknown. Here we aimed at deciphering the role of NAC neurons in the encoding and retrieval of opiate withdrawal memory. Chronic single neuron and local field potentials recordings were performed in morphine-dependent rats and placebo controls. Animals were subjected to an unbiased conditioned placed aversion protocol with one compartment (CS+) paired with naloxone-precipitated withdrawal, a second compartment with saline injection (CS−), and a third being neutral (no pairing). After conditioning, animals displayed a typical place aversion for CS+ and developed a preference for CS− characteristic of safety learning. We found that distinct NAC neurons code for CS+ or CS−. Both populations also displayed highly specific oscillatory dynamics, CS+ and CS− neurons, respectively, following 80 Hz (G80) and 60 Hz (G60) local field potential gamma rhythms. Finally, we found that the balance between G60 and G80 rhythms strongly correlated both with the ongoing behavior of the animal and the strength of the conditioning. We demonstrate here that the aversive and preferred environments are underpinned by distinct groups of NAC neurons as well as specific oscillatory dynamics. This suggest that G60/G80 interplay—established through the conditioning process—serves as a robust and versatile mechanism for a fine coding of the environment emotional weight.

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GABAB receptors play a modulatory role in the mechanisms underlying drug addiction, sleep problems, and aging; however, there are few studies addressing their relationship. Therefore, this study aimed to examine whether blockade of these receptors affects methamphetamine (METH) reward memory in adult and adolescent rapid-eye movement sleep deprived (RSD) rats. Adolescent and adult male Wistar rats were subjected to RSD for seven days. They were then conditioned to receive methamphetamine (METH; 2 mg/kg, ip) during an eight-day conditioning period. METH reward memory was then reactivated during a retrieval trial and the GABAB receptor agonist baclofen (2.5 or 5 mg/kg, ip) was injected prior to the retrieval trial. Afterward, animals were retested for the expression of conditioned place preference (CPP) and hippocampal expression of GABAB receptors. Baclofen dose-dependently decreased the retrieval of METH reward memory in control and RSD adult and adolescent rats, but its effects were stronger at the higher dose. Moreover, we found stronger effects of baclofen in adolescent animals than in adult ones. In addition, baclofen at its higher dose decreased GABAB overexpression in the hippocampus of adolescent rats, but not in adult rats. These findings shed new light on the mechanisms underlying the role of GABAB receptors in the retrieval of METH reward memory and highlight the importance of considering age and sleep patterns in understanding addiction. Further research could potentially lead to the development of therapeutics for individuals struggling with METH addiction.

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ABSTRACT Drug‐associated contexts and discrete cues can trigger motivational states responsible for drug‐seeking behavior and relapse. In preclinical research, drug‐free conditioned hyperactivity has been used to investigate the expression of memories associated with psychostimulant drug effects. Addictive drugs can produce long‐lasting sensitization to their psychomotor actions, a phenomenon known as behavioral sensitization. The neuroplasticity underlying behavioral sensitization appears to be involved in pathological drug pursuit and abuse. In the present study we evaluated drug‐free, context‐dependent hyperactivity in DBA/2 J mice previously treated with cocaine and explored whether this conditioned effect was related to behavioral sensitization. Given the role of noradrenergic (NA) neurotransmission in memory retrieval, consolidation and reconsolidation processes, we also investigated whether conditioned hyperactivity in a drug‐free state was mediated by NA receptors. Animals underwent a sensitization protocol with six cocaine injections (0, 5, 10 or 20 mg/kg) paired to a particular floor cue. Three days after this sensitization phase, all animals were exposed to the same familiar floor environment without drug treatment. A second test with an unfamiliar floor was conducted 24 h later. Conditioned hyperactivity was also explored after one or three cocaine pairings and was evaluated for its duration (with repeated familiar vs. unfamiliar floor tests). In a series of pharmacological experiments, we evaluated the effects propranolol (a non‐selective antagonist of &bgr;1‐ and &bgr;2‐receptors) and prazosin (&agr;1‐receptor antagonist) on conditioned hyperactivity. Cocaine treatment produced both robust sensitization and drug‐free conditioned hyperactivity, an effect that lasted up to 17 days (with cocaine 20 mg/kg). A significant correlation between the magnitude of cocaine sensitization and the level of conditioned hyperactivity was found. Propranolol, but not prazosin, blocked context‐dependent hyperlocomotion in a drug‐free state. Our data, together with a vast body of literature, indicate that the NA system plays a key role in the retrieval and behavioral expression of drug‐associated memories. HighlightsCocaine‐sensitized animals show drug‐free, context‐dependent hyperactivity.The magnitude of cocaine‐induced sensitization predicts conditioned hyperactivity.&bgr;‐1 and &bgr;‐2, but not &agr;1‐noradrenergic receptors mediate conditioned hyperactivity

Relapse, a critical issue in alcohol addiction, can be attenuated by disruption of alcohol-associated memories. Memories are thought to temporarily destabilize upon retrieval during the reconsolidation process. Here, we provide evidence for unique transcriptional dynamics underpinning alcohol memory reconsolidation. Using a mouse place-conditioning procedure, we show that alcohol-memory retrieval increases the mRNA expression of immediate-early genes in the dorsal hippocampus and medial prefrontal cortex, and that alcohol seeking is abolished by post-retrieval non-specific inhibition of gene transcription, or by downregulating ARC expression using antisense-oligodeoxynucleotides. However, since retrieval of memories for a natural reward (sucrose) also increased the same immediate-early gene expression, we explored for alcohol-specific transcriptional changes using RNA-sequencing. We revealed a unique transcriptional fingerprint activated by alcohol memories, as the expression of this set of plasticity-related genes was not altered by sucrose-memory retrieval. Our results suggest that alcohol memories may activate two parallel transcription programs: one is involved in memory reconsolidation in general, and another is specifically activated during alcohol-memory processing.

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Exposure to smoking-related stimuli may induce the reconsolidation of smoking-related memories in smokers. Research has proposed that extinction applied after the retrieval of a smoking memory may inhibit reconsolidation and prevent craving. The aim of this study was to test the effect of postretrieval extinction (PRE) on the reconsolidation of smoking memory by using a virtual reality (VR) simulation in smokers. On the day 1 session, the study exposed 46 smokers to a neutral and then to a smoking VR scenario under a fixed-block protocol. On day 2, the study randomized participants into three groups (G) and exposed them to a 15-s VR immersion in smoking (G1, G3) or neutral (G2) scenario for memory retrieval. After 15 min, the study exposed G1 and G2 to a VR PRE during the temporal window of memory vulnerability, whereas the study exposed G3 to extinction immediately after retrieval. On day 3, the study exposed all groups to neutral and smoking scenarios similar to day 1. All groups significantly increased craving for cigarettes after exposure to the smoking scenario on day 1 (p < 0.01). On day 3, VR PRE after a 15-second VR smoking memory retrieval was able to inhibit reconsolidation in G1, but not in G3 exposed to PRE before the window of vulnerability, or in G2 not exposed to the smoking memory retrieval. These findings show the superiority of VR PRE after smoking memory retrieval compared to a standard extinction procedure.

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The formation of memories is a complex, multi-scale phenomenon, especially when it involves integration of information from various brain systems. We have investigated the differences between a novel and consolidated association of spatial cues and amphetamine administration, using an in-situ hybridisation method to track the short-term dynamics during the recall testing. We have found that remote recall group involves smaller, but more consolidated groups of neurons, which is consistent with their specialisation. By employing machine learning analysis, we have shown this pattern is especially pronounced in the VTA; furthermore, we also uncovered significant activity patterns in retrosplenial and prefrontal cortices, as well as in the DG and CA3 subfields of the hippocampus. The behavioural propensity towards the associated localisation appears to be driven by the nucleus accumbens, however, further modulated by a trio of the amygdala, VTA and hippocampus, as the trained association is confronted with test experience. These results show that memory mechanisms must be modelled considering individual differences in motivation, as well as covering dynamics of the process.

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Cocaine use and relapse involves learned associations between cocaine-associated environmental contexts and discrete stimuli and cocaine effects. Initially, these contextual and discrete cues undergo memory consolidation after being paired with cocaine exposure. During abstinence, cocaine cue memories can undergo memory reconsolidation after cue exposure without the drug. We used a conditioned place preference (CPP) procedure in rats to study the role of neuronal protein kinase cyclin-dependent kinase 5 (Cdk5) in consolidation and reconsolidation of cocaine cue memories. We found that the expression of cocaine CPP in drug-free tests 1 d after CPP training (four pairings of 10 mg/kg cocaine with one context and four pairings of saline with a different context) increased Cdk5 activity, and levels of the Cdk5 activator p35 in basolateral but not central amygdala. We also found that basolateral (but not central) amygdala injections of the Cdk5 inhibitor β-butyrolactone (100 ng/side) immediately (but not 6 h) after cocaine–context pairings during training prevented subsequent cocaine CPP expression. After training, acute basolateral (but not central) amygdala β-butyrolactone injections immediately before testing prevented the expression of cocaine CPP; this effect was also observed on a second test performed 1 d later, suggesting an effect on reconsolidation of cocaine cue memories. In support, basolateral β-butyrolactone injections, given immediately (but not 6 h) after a single exposure to the cocaine-paired context, prevented cocaine CPP expression 1 and 14 d after the injections. Results indicate that basolateral amygdala Cdk5 activity is critical for consolidation and reconsolidation of the memories of cocaine-associated environmental cues.

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Persistent drug seeking/taking behavior involves the consolidation of memory. With each drug use, the memory may be reactivated and reconsolidated to maintain the original memory. During reactivation, the memory may become labile and susceptible to disruption; thus, molecules involved in plasticity should influence acquisition and/or reconsolidation. Recently, matrix metalloproteinases (MMPs) have been shown to influence neuronal plasticity, presumably by their regulation of extracellular matrix (ECM) molecules involved in synaptic reorganization during learning. We hypothesized that inhibition of MMP activity would impair the acquisition and/or reconsolidation of cocaine-conditioned place preference (CPP) in rats. Intracerebral ventricular (i.c.v.) microinjection of a broad spectrum MMP inhibitor, FN-439, prior to cocaine training suppressed acquisition of CPP and attenuated cocaine-primed reinstatement in extinguished animals. In a separate experiment, the cocaine memory was reactivated on two consecutive days with a cocaine priming injection. On these two days, artificial cerebral spinal fluid (aCSF) or FN-439 was administered either 30 min prior to or 1 min after cocaine-primed reinstatement sessions. Infusion of FN-439 partially impaired retrieval of the cocaine-associated context when given 30 min prior to cocaine. In both groups, however, FN-439 suppressed reinstatement compared with controls on the third consecutive test for cocaine-primed reinstatement, when no FN-439 was given. Control experiments demonstrated that two injections of FN-439 + cocaine given in the home cage, or of FN-439 + saline priming injections in the CPP chambers did not disrupt subsequent cocaine-primed reinstatement. These results show for the first time that (1) MMPs play a critical role in acquisition and reconsolidation of cocaine-induced CPP, and (2) rats demonstrate apparent disruption of reconsolidation by an MMP inhibitor after extinction and while they are under the influence of cocaine during reinstatement.

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Relapse to alcohol abuse is often caused by exposure to potent alcohol-associated cues. Therefore, disruption of the cue-alcohol memory can prevent relapse. It is believed that memories destabilize and become prone for updating upon their reactivation through retrieval, and then re-stabilize within 6 h during a “reconsolidation” process. We recently showed that relapse to cocaine seeking could be prevented by counterconditioning the cocaine-cues with aversive outcomes following cocaine-memory retrieval, in a place conditioning paradigm. However, to better model addiction-related behaviors, self-administration models are necessary. Here, we demonstrate that relapse to alcohol seeking can be prevented by aversive counterconditioning conducted during alcohol-memory reconsolidation, in conditioned place preference (CPP) and operant self-administration paradigms, in mice and rats, respectively. We found that the reinstatement of alcohol-CPP was abolished only when aversive counterconditioning with water-flooding was given shortly after alcohol-memory retrieval. Furthermore, rats trained to lever-press for alcohol showed decreased context-induced renewal of alcohol-seeking responding when the lever-pressing was counterconditioned with foot-shocks, shortly, but not 6 h, after memory retrieval. These results 0suggest that aversive counterconditioning can prevent relapse to alcohol seeking only when performed during alcohol-memory reconsolidation, presumably by updating, or replacing, the alcohol memory with aversive information. Also, we found that aversive counterconditioning preceded by alcohol-memory retrieval was characterized by upregulation of brain-derived neurotrophic factor (Bdnf) mRNA expression in the medial prefrontal cortex, suggesting that Bdnf plays a role in the memory updating process.

Adolescents are at increased risk to develop substance use disorders and suffer from relapse throughout life. Targeted weakening of drug-associated memories has been shown to reduce relapse-like behavior in adult rats, however this process has been understudied in adolescents. We aimed to examine whether adolescent-formed, cocaine-associated memories could be manipulated via reconsolidation mechanisms. To accomplish this objective, we used an abbreviated operant cocaine self-administration paradigm (ABRV Coc-SA). Adult and adolescent rats received jugular catheterization surgery followed by ABRV Coc-SA in a distinct context for 2 h, 2×/day over 5 days. Extinction training (EXT) occurred in a second context for 2 h, 2×/day over 4 days. To retrieve cocaine-context memories, rats were exposed to the cocaine-paired context for 15 min, followed by subcutaneous injection of vehicle or the protein synthesis inhibitor cycloheximide (2.5 mg/kg). Two additional EXT sessions were conducted before a 2 h reinstatement test in the cocaine-paired context to assess cocaine-seeking behavior. We find that both adult and adolescent cocaine-exposed rats show similar levels of cocaine-seeking behavior regardless of post-reactivation treatment. Our results suggest that systemic treatment with the protein synthesis inhibitor cycloheximide does not impair reconsolidation of cocaine-context memories and subsequent relapse during adulthood or adolescence.

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Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated memories. Here we report a similar disruption of memories associated with amphetamine, but not cocaine or morphine, by NMIIi. Reconsolidation appeared to be disrupted with cocaine. Unlike in the amygdala, methamphetamine-associated memory storage was not disrupted by NMIIi in the hippocampus, nucleus accumbens, or orbitofrontal cortex. NMIIi in the hippocampus did appear to disrupt reconsolidation. Identification of the unique mechanisms responsible for NMII-mediated, amygdala-dependent disruption of memory storage associated with the amphetamine class may enable induction of retrieval-independent vulnerability to other pathological memories.

Drug-related memories can hinder abstinence goals in drug addiction. Promoting nondrugmemories via ventromedial prefrontal cortex (vmPFC)- and amygdala-guided extinctionyields mixed success. Postretrieval extinction (RE) destabilizes and updates memoriesduring reconsolidation, improving extinction. Supplementing RE, we tested methylphenidate(MPH), a dopamine agonist that promotes PFC-dependent learning and memory in cocaineuse disorder (CUD). In a proof-of-concept double-blind randomized clinical trialusing a within-subjects design, participants received oral MPH (20 mg) or placebobefore the retrieval of some of the conditioned stimuli (CS) (i.e., reminded CS+ vs.nonreminded CS+) followed by extinction; lab-simulated drug-seeking was measuredthe following day. Lower vmPFC activity following nonreminded CS+ (standardextinction) under placebo replicated the putative impairments in CUD; separately, RE (trend) and MPH conditions recruited the vmPFC, and RE's vmPFC-reliance correlatedwith drug-seeking only under placebo. Crucially, MPH-combined RE normalized cortico-limbicprocessing, bypassing the vmPFC and its amygdala connectivity. Pharmacologically-enhanced drug memory modulation may inform intervention development for addictionrecovery.

Chromatin modification is a crucial mechanism in several important phenomena in the brain, including drug addiction. Persistence of drug craving and risk of relapse could be attributed to drug-induced epigenetic mechanisms that seem to be candidates explaining long-lasting drug-induced behaviour and molecular alterations. Histone acetylation has been proposed to regulate drug-seeking behaviours and the extinction of rewarding memory of drug taking. In this work, we studied the epigenetic regulation during conditioned place aversion and after extinction of aversive memory of opiate withdrawal. Through immunofluorescence assays, we assessed some epigenetic marks (H4K5ac and p-Brd4) in crucial areas related to memory retrieval -basolateral amygdala (BLA) and hippocampus-. Additionally, to test the degree of transcriptional activation, we evaluated the immediate early genes (IEGs) response (Arc, Bdnf, Creb, Egr-1, Fos and Nfkb) and Smarcc1 (chromatin remodeler) through RT-qPCR in these nuclei. Our results showed increased p-Brd4 and H4K5ac levels during aversive memory retrieval, suggesting a more open chromatin state. However, transcriptional activation of these IEGs was not found, therefore suggesting that other secondary response may already be happening. Additionally, Smarcc1 levels were reduced due to morphine chronic administration in BLA and dentate gyrus. The activation markers returned to control levels after the retrieval of aversive memories, revealing a more repressed chromatin state. Taken together, our results show a major role of the tandem H4K5ac/p-Brd4 during the retrieval of aversive memories. These results might be useful to elucidate new molecular targets to improve and develop pharmacological treatments to address addiction and to avoid drug relapse.

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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.

Reconsolidation of heroin-associated memory is an independent memory process that occurs following retrieval, which is essential for the sustained capacity of an associative drug stimulus to precipitate heroin-seeking. Extracellular signal-regulated kinase (ERK) in the basolateral amygdala (BLA) mediates the reconsolidation of drug memory. In the present study, we utilized a rat model of drug craving and relapse to verify the hypothesis that the reconsolidation of heroin-associated memory requires ERK in an instrumental heroin-seeking behavior, focusing on the BLA brain region, which is crucial for synaptic plasticity and memory processes. We found that bilateral intra-BLA infusions of U0126 (1 μg/0.5 μl), an ERK inhibitor, immediately after retrieving heroin-associated memory significantly reduced cue-induced and drug-induced reinstatement and spontaneous recovery of heroin-seeking compared to the vehicle. Furthermore, this inhibitory effect was related to the characteristic of reconsolidation. Conversely, no effect was observed on the heroin-seeking behavior when the intra-BLA infusion of U0126 was administered 6 h after the heroin-associated memory retrieval or without memory retrieval. Together, these data suggest that disrupting the reconsolidation of heroin-associated memory via an ERK inhibitor may serve as a promising option for treating relapse in opiate addicts.

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.

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A distributed limbic-corticostriatal circuitry is implicated in cue-induced drug craving and relapse. Exposure to drug-paired cues not only precipitates relapse, but also triggers the reactivation and reconsolidation of the cue-drug memory. However, the limbic cortical-striatal circuitry underlying drug memory reconsolidation is unclear. The aim of this study was to investigate the involvement of the nucleus accumbens core and the basolateral amygdala in the reconsolidation of a cocaine-conditioned stimulus-evoked memory. Antisense oligodeoxynucleotides (ASO) were infused into each structure to knock down the expression of the immediate-early gene zif268, which is known to be required for memory reconsolidation. Control infusions used missense oligodeoxynucleotides (MSO). The effects of zif268 knockdown were measured in two complementary paradigms widely used to assess the impact of drug-paired CSs upon drug seeking: the acquisition of a new instrumental response with conditioned reinforcement and conditioned place preference. The results show that both intranucleus accumbens core and intrabasolateral amygdala zif268 ASO infusions at memory reactivation impaired the reconsolidation of the memory underlying a cocaine-conditioned place preference. However, knockdown of zif268 in the nucleus accumbens at memory reactivation had no effect on the memory underlying the conditioned reinforcing properties of the cocaine-paired CS measured subsequently, and this is in contrast to the marked impairment observed previously following intrabasolateral amygdala zif268 ASO infusions. These results suggest that both the basolateral amygdala and nucleus accumbens core are key structures within limbic cortical-striatal circuitry where reconsolidation of a cue-drug memory occurs. However reconsolidation of memory representations formed during Pavlovian conditioning are differentially localized in each site.

Relapse to drug taking induced by exposure to cues associated with drugs of abuse is a major challenge to the treatment of drug addiction. Previous studies indicate that drug seeking can be inhibited by disrupting the reconsolidation of a drug-related memory. Stress plays an important role in modulating different stages of memory including reconsolidation, but its role in the reconsolidation of a drug-related memory has not been investigated. Here, we examined the effects of stress and corticosterone on reconsolidation of a drug-related memory using a conditioned place preference (CPP) procedure. We also determined the role of glucocorticoid receptors (GRs) in the basolateral amygdala (BLA) in modulating the effects of stress on reconsolidation of this memory. We found that rats acquired morphine CPP after conditioning, and that this CPP was inhibited by stress given immediately after re-exposure to a previously morphine-paired chamber (a reconsolidation procedure). The disruptive effect of stress on reconsolidation of morphine related memory was prevented by inhibition of corticosterone synthesis with metyrapone or BLA, but not central amygdala (CeA), injections of the glucocorticoid (GR) antagonist RU38486 [(11,17)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one]. Finally, the effect of stress on drug related memory reconsolidation was mimicked by systemic injections of corticosterone or injections of RU28362 [11,17-dihydroxy-6-methyl-17-(1-propynyl)androsta-1,4,6-triene-3-one] (a GR agonist) into BLA, but not the CeA. These results show that stress blocks reconsolidation of a drug-related memory, and this effect is mediated by activation of GRs in the BLA.

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Recent research suggests that drug-related memories are reactivated after exposure to environmental cues and may undergo reconsolidation, a process that can strengthen memories. Conversely, reconsolidation may be disrupted by certain pharmacological agents such that the drug-associated memory is weakened. Several studies have demonstrated disruption of memory reconsolidation using a drug-induced conditioned place preference (CPP) task, but no studies have explored whether cocaine-associated memories can be similarly disrupted in cocaine self-administering animals after a cocaine priming injection, which powerfully reinstates drug-seeking behavior. Here we used cocaine-induced CPP and cocaine self-administration to investigate whether the N-methyl-D-aspartate receptor antagonist (+)-5methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) given just prior to reactivation sessions would suppress subsequent cocaine-primed reinstatement (disruption of reconsolidation). Systemic injection of MK-801 (0.05 or 0.20 mg/kg administered intraperitoneally) in rats just prior to reactivation of the cocaine-associated memory in the CPP context attenuated subsequent cocaine-primed reinstatement, while no disruption occurred in rats that did not receive reactivation in the CPP context. However, in rats trained to self-administer cocaine, systemic administration of MK-801 just prior to either of two different types of reactivation sessions had no effect on subsequent cocaine-primed reinstatement of lever-pressing behavior. Thus, systemic administration of MK-801 disrupted the reconsolidation of a cocaine-associated memory for CPP but not for self-administration. These findings suggest that cocaine-CPP and self-administration do not use similar neurochemical processes to disrupt reconsolidation or that cocaine-associated memories in self-administering rats do not undergo reconsolidation, as assessed by lever-pressing behavior under cocaine reinstatement conditions.

The susceptibility to drug cravings evoked by stimuli poses a formidable hurdle in the treatment of addiction and the prevention of relapse. Pharmacological interventions targeting drug‐associated memories hold promise for curbing relapse by impeding the process of memory reconsolidation, predominantly governed by cAMP signalling. Exchange Protein Activated by cAMP (Epac) serves as a distinctive mediator of cAMP signalling, which has been implicated in reinforcing the effects of cocaine and facilitating the acquisition. Nonetheless, the role of Epac in heroin‐related memory and the subsequent seeking behaviour remains enigmatic. In this study, we explored the impact of Epac activation on the reconsolidation process of drug‐related memories associated with heroin self‐administration. Over the course of 10 consecutive days, rats underwent training, wherein they acquired the behaviour of nose poking to obtain heroin accompanied by a tone + light cue. This nose‐poking behaviour was subsequently extinguished when heroin infusion and cue presentation were discontinued. Subsequently, we administered 8‐pCPT‐cAMP (8‐CPT), an Epac‐specific activator, into the basolateral amygdala at various time points, either in the presence or absence of a conditioned stimulus. Our findings demonstrate that administering 8‐CPT immediately after memory retrieval effectively reduces cue‐ and heroin‐induced reinstatement, with the observed effects persisting significantly for a minimum of 28 days. However, infusion of 8‐CPT for a duration of 6 h following the memory retrieval trial, or without it altogether, had no discernible impact. Thus, these findings strongly suggest that Epac activation can disrupt the reconsolidation of heroin‐associated memory, thereby diminishing the reinstatement of heroin‐seeking behaviour.

Conditioned cue-induced relapse to drug seeking is a major challenge to the treatment of drug addiction. It has been proposed that D-cycloserine might be useful in the prevention of relapse by reducing the conditioned reinforcing properties of drug-associated stimuli through facilitation of extinction. Here we show that intrabasolateral amygdala infusions of D-cycloserine in fact potentiate the reconsolidation of stimulus-cocaine memories to increase cue-induced relapse to drug seeking in rats with an extensive drug self-administration history. This elevation of cocaine seeking was correlated with an increase in the expression of the reconsolidation-associated gene zif268.

Drug addiction can be seen as a disorder of maladaptive learning characterized by relapse. Therefore, disrupting drug-related memories could be an approach to improving therapies for addiction. Pioneering studies over the last two decades have revealed that consolidated memories are not static, but can be reconsolidated after retrieval, thereby providing candidate pathways for the treatment of addiction. The limbic–corticostriatal system is known to play a vital role in encoding the drug memory engram. Specific structures within this system contribute differently to the process of memory reconsolidation, making it a potential target for preventing relapse. In addition, as molecular processes are also active during memory reconsolidation, amnestic agents can be used to attenuate drug memory. In this review, we focus primarily on the brain structures involved in storing the drug memory engram, as well as the molecular processes involved in drug memory reconsolidation. Notably, we describe reports regarding boundary conditions constraining the therapeutic potential of memory reconsolidation. Furthermore, we discuss the principles that could be employed to modify stored memories. Finally, we emphasize the challenge of reconsolidation-based strategies, but end with an optimistic view on the development of reconsolidation theory for drug relapse prevention.

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Association between the reward caused by consuming drugs and the context in which they are consumed is essential in the formation of morphine-induced conditioned place preference (CPP). Glucocorticoid receptor (GRs) activation in different regions of the brain affects reward-based reinforcement and memory processing. A wide array of studies have demonstrated that blockage of GRs in some brain areas can have an effect on reward-related memory; however, to date there have been no systematic studies about the involvement of glucocorticoids (GCs) in morphine-related reward memory. Here, we used the GR antagonist RU38486 to investigate how GRs blockage affects the sensitization and CPP behavior during different phases of reward memory included acquisition, retrieval and reconsolidation. Interestingly, our results showed RU38486 has the ability to impair the acquisition, retrieval and reconsolidation of reward-based memory in CPP and sensitization behavior. But RU38486 by itself cannot induce CPP or conditioned place aversion (CPA) behavior. Our data provide a much more complete picture of the potential effects that glucocorticoids have on the reward memory of different phases and inhibit the sensitization behavior.

BACKGROUND Craving is a key challenge in treating methamphetamine use disorder (MUD). The memory reconsolidation theory indicates that interference with MUD after drug memory retrieval helps to reduce craving. Previous studies have demonstrated the importance of the hippocampus in memory consolidation, but traditional non-invasive interventions cannot effectively locate and intervene in the hippocampus. Although tTIS can accurately intervene in deep brain regions, it is still unknown whether tTIS intervention on the MUD hippocampus is effective in reducing craving. METHOD A total of 40 male participants with MUD were randomized to active or sham tTIS. Active tTIS delivered a 10 Hz electric field to the hippocampus for 20 min per day over 10 consecutive days, while sham stimulation lasted only 1 min per day during the same period. We also assessed its effects on craving, cognitive function and emotional symptoms at baseline, post intervention and one month follow-up. RESULTS A two-way repeated-measures analysis of variances (ANOVAs) on drug cue-induced craving revealed a significant group × time interaction effect (F (2, 108) = 5.652, P = 0.005). Post hoc paired t-test indicated a significant decrease in craving in the active tTIS group (t = 5.04, P = 0.002) after the intervention and one month follow-up (t = 6.04, P < 0.001). In contrast, no significant changes were observed in the sham group. CONCLUSIONS In this trial, 10 Hz tTIS was effective for METH craving reduction in MUD. Further trials are needed to explore neural mechanisms of tTIS.

The majority of smokers relapse even after successfully quitting because of the craving to smoking after unexpectedly re-exposed to smoking-related cues. This conditioned craving is mediated by reward memories that are frequently experienced and stubbornly resistant to treatment. Reconsolidation theory posits that well-consolidated memories are destabilized after retrieval, and this process renders memories labile and vulnerable to amnestic intervention. This study tests the retrieval reconsolidation procedure to decrease nicotine craving among people who smoke. In this study, 52 male smokers received a single dose of propranolol ( n  = 27) or placebo ( n  = 25) before the reactivation of nicotine-associated memories to impair the reconsolidation process. Craving for smoking and neural activity in response to smoking-related cues served as primary outcomes. Functional magnetic resonance imaging was performed during the memory reconsolidation process. The disruption of reconsolidation by propranolol decreased craving for smoking. Reactivity of the postcentral gyrus in response to smoking-related cues also decreased in the propranolol group after the reconsolidation manipulation. Functional connectivity between the hippocampus and striatum was higher during memory reconsolidation in the propranolol group. Furthermore, the increase in coupling between the hippocampus and striatum positively correlated with the decrease in craving after the reconsolidation manipulation in the propranolol group. Propranolol administration before memory reactivation disrupted the reconsolidation of smoking-related memories in smokers by mediating brain regions that are involved in memory and reward processing. These findings demonstrate the noradrenergic regulation of memory reconsolidation in humans and suggest that adjunct propranolol administration can facilitate the treatment of nicotine dependence. The present study was pre-registered at ClinicalTrials.gov (registration no. ChiCTR1900024412).

Abstract Background Drug addiction is a chronic and recurrent brain disease. Addictive substances can cause changes in brain circuits and may be integrated into the memory system. Drug addiction consists of different phases, beginning when recreational use escalates to compulsive use and then cycles through withdrawal, and relapse. A relapse is a return to drinking or drug use after attempts have previously been made to stop. The prevention of relapses is perhaps the most fundamental task in addiction recovery. Repeated retrieval by the cue without reward stimulant reduces the behavioral response through a process called extinction. This learning is the fundamental principle underlying many cognitive- behavioral psychotherapeutic treatments. Yet behavioral change may be difficult to sustain, and relapse is not uncommon, even after successful treatment. Memory updating was applied to substance use problems by weakening the ability of drug-associated triggers to elicit substance use[1]. Stress can potentially affect all cognitive phases involved in memory function such as the process of memory storage, retrieval or/and consolidation. Stress prior to extinction might not only enhance the consolidation of extinction memory, like post-extinction stress does, but also make it less context- dependent[2]. Aims & Objectives 1) Whether stress combined with extinction learning disrupts consolidated memory to suppress cocaine relapse. 2) What is the mechanism of stress combined with extinction learning suppressing drug seeking behavior. Method The self-administration of cocaine was used as an animal model for addictive memory. A combination of techniques, including immunofluorescence, fiber optic recording, brain slice patch-clamp recordings, and Golgi staining, was employed to explore the mechanism of stress combined with extinction in addictive memory. Results (1) The drug-priming test following self-administration extinction training suggested that rats exposed to footshock before extinction training (FE group) had a lower number of active nosepokes compared to extinction group (E group). Interestingly, in conditioned place avoidance test, footshock did not elicit an aversive response. (2) Fiber optic recording results showed excitatory neuron in LHb were more active in FE group during drug-priming test. Electrophysiological in vitro results suggested a significant increase in action potential firing and reduction of the threshold of the injected current to trigger the action potential in LHb. (3) Chemogenetic activation of neuron activity in LHb combined with extinction training effectively facilitated the elimination of cocaine addiction memory and reduced psychological craving. (4) Chemogenetic activation of neuron activity in LHb increased cfos expression in RMTg. Activation of LHb-RMTg also facilitated extinction and inhibited relapse. Activation of LHb-RMTg circuit could mimic the effect of stress combined with extinction in inhibiting relapse. Discussion & Conclusion This study demonstrateed that stress combination with extinction training may promote the extinction of addictive memory and inhibit relapse by reshaping activity of neurons in the LHb-RMTg circuit. References 1.Xue YX, Luo YX, Wu P, et al. A memory retrieval-extinction procedure to prevent drug craving and relapse. Science. 2012;336(6078):241-245. doi:10.1126/science.1215070 2.Sandi C, Pinelo-Nava MT. Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast. 2007;2007:78970. doi:10.1155/2007/78970

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Classic lesion case-control studies suggest minimal involvement of the medial temporal lobe (MTL) in visual working memory (VWM), particularly for simple stimulus features like color or orientation. However, recent intracranial recordings implicate the MTL - especially the hippocampus - in supporting VWM precision by distinguishing similar visual features to reduce representational variability during short retention intervals. Meanwhile, reports that MTL activity scales with VWM set size have raised the possibility that the MTL contributes not only to the quality but also the quantity of retained VWM content - an idea motivated by models positing a unitary memory strength metric to account for behavioral expressions of both VWM quantity and quality. To clarify the extent to which MTL lesions affect VWM quality, quantity, or both, we examined VWM recall performance in 40 neurological cases with drug-resistant epilepsy before and after their brain surgery for seizure treatment. Of these, 19 had lesions involving the hippocampus, while 21 had either no lesions or lesions outside the hippocampus. Using a controlled VWM task with fixed set size and minimal non-target recall errors, we modeled participants' recall responses to estimate recall variability as an inverse measure of VWM precision and the probability of recall success as the proportion of trials not attributable to failed, uniform recall responses. We found that lesions affecting the hippocampus in the MTL led to a significant increase in recall variability, indicating reduced VWM precision after surgery. Voxel-based lesion-symptom mapping further revealed a robust association between hippocampal damage and increased recall variability, even after controlling for overall brain lesion volume. In contrast, total lesion volume - but not hippocampal lesion extent - predicted reduced recall success rate, suggesting that broader lesion burden constrains how much content is retained, resulting in more failed recall responses. An alternative model assuming a unitary memory strength metric captured the overall performance decline with increasing total lesion volume but could not account for the MTL-specific effects. Together, these findings highlight the MTL's role in preserving the fidelity - rather than the mere presence - of VWM representations. They challenge models that treat VWM quality and quantity as interchangeable consequences of a single underlying memory strength parameter. By identifying distinct neural correlates for each component, our results point to VWM precision as a sensitive behavioral marker - one that may be useful for tracking functional changes in individuals with memory impairment, including those with focal brain lesions.

Reconsolidation is a process by which memories are destabilized, updated, and then restabilized. Strong memories are resistant to undergoing reconsolidation. Here, we addressed whether an overtrained fear memory could be made susceptible to reconsolidation by first extinguishing, and then renewing, the memory. Rats were trained with ten tone-footshock pairings, followed by eight days of tone extinction in the training context. The next day, rats were placed into a second context and memory for the tone was renewed/reactivated with a single tone presentation. Immediately following reactivation, rats received an injection of midazolam or vehicle. Rats were then tested for freezing to the tone in a third context. Midazolam had no effect in rats that did not undergo tone extinction, but significantly attenuated freezing to the tone in extinguished rats. Thus, rats that received tone extinction underwent tone memory reconsolidation following its renewal. In a second experiment, we administered the reactivation session and midazolam injections prior to extinction. Midazolam had no effect and rats extinguished at a rate similar to controls. These data suggest that strong emotional memories are capable of updating following weakening of memory expression through extinction.

Human studies have consistently shown that drugs of abuse affect memory function. The psychostimulants amphetamine and the “bath salt” 3,4-methylenedioxypyrovalerone (MDPV) increase brain monoamine levels through a similar, yet not identical, mechanism of action. Findings indicate that amphetamine enhances the consolidation of memory for emotional experiences, but still MDPV effects on memory function are underinvestigated. Here, we tested the effects induced by these two drugs on generalization of fear memory and their relative neurobiological underpinnings. To this aim, we used a modified version of the classical inhibitory avoidance task, termed inhibitory avoidance discrimination task. According to such procedure, adult male Sprague–Dawley rats were first exposed to one inhibitory avoidance apparatus and, with a 1-min delay, to a second apparatus where they received an inescapable footshock. Forty-eight hours later, retention latencies were tested, in a randomized order, in the two training apparatuses as well as in a novel contextually modified apparatus to assess both strength and generalization of memory. Our results indicated that both amphetamine and MDPV induced generalization of fear memory, whereas only amphetamine enhanced memory strength. Co-administration of the β-adrenoceptor antagonist propranolol prevented the effects of both amphetamine and MDPV on the strength and generalization of memory. The dopaminergic receptor blocker cis-flupenthixol selectively reversed the amphetamine effect on memory generalization. These findings indicate that amphetamine and MDPV induce generalization of fear memory through different modulations of noradrenergic and dopaminergic neurotransmission.

Long-term memory formation is generally assumed to involve the permanent storage of recently acquired memories, making them relatively insensitive to disruption, a process referred to as memory consolidation. However, when retrieved under specific circumstances, consolidated fear memories are thought to return to a labile state, thereby opening a window for modification (e.g., attenuation) of the memory. Several interventions during a critical time frame after this destabilization seem to be able to alter the retrieved memory, for example by pharmacologically interfering with the restabilization process, either by direct protein synthesis inhibition or indirectly, using drugs that can be safely administered in patients (e.g., propranolol). Here, we find that, contrary to expectations, systemic pharmacological manipulations in auditory fear-conditioned rats do not lead to drug-induced post-retrieval amnesia. In a series of well-powered auditory fear conditioning experiments (four with propranolol, 10 mg/kg, two with rapamycin, 20–40 mg/kg, one with anisomycin, 150 mg/kg and cycloheximide, 1.5 mg/kg), we found no evidence for reduced cued fear memory expression during a drug-free test in adult male Sprague-Dawley rats that had previously received a systemic drug injection upon retrieval of the tone fear memory. All experiments used standard fear conditioning and reactivation procedures with freezing as the behavioral read-out (conceptual or exact replications of published reports) and common pharmacological agents. Additional tests confirmed that the applied drug doses and administration routes were effective in inducing their conventional effects on expression of fear (propranolol, acutely), body weight (rapamycin, anisomycin, cycloheximide), and consolidation of extinction memories (cycloheximide). In contrast with previously published studies, we did not find evidence for drug-induced post-retrieval amnesia, underlining that this effect, as well as its clinical applicability, may be considerably more constrained and less readily reproduced than what the current literature would suggest.

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Current pharmacological and psychological treatments for disorders of emotional memory only dampen the affective response while leaving the original fear memory intact. Under adverse circumstances, these original memories regain prominence, causing relapses in many patients. The (re)discovery in neuroscience that after reactivation consolidated fear memories may return to a transient labile state, requiring a process of restabilization in order to persist, offers a window of opportunity for modifying fear memories with amnestic agents. This process, known as memory reconsolidation, opens avenues for developing a revolutionary treatment for emotional memory disorders. The reconsolidation intervention challenges the dominant pharmacological and psychological models of treatment: it is only effective when the amnestic drug is given in conjunction with memory reactivation during a specific time window, and a modification of cognitive processes is a boundary condition for changing fear. Notwithstanding the dramatic effects of targeting memory reconsolidation in the laboratory (i.e. proof of principle), the greatest hurdle to overcome is that the success of the manipulation depends on subtle differences in the reactivation procedure. These experimental parameters cannot be easily controlled in clinical practice. In harnessing the clinical potential of memory reconsolidation, a heuristic for bi-directionally translating behavioural neuroscience and clinical science is proposed. This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’.

Repeated drug use has long-lasting effects on plasticity throughout the brain's reward and memory systems. Environmental cues that are associated with drugs of abuse can elicit craving and relapse, but the neural circuits responsible for driving drug-cue-related behaviors have not been well delineated, creating a hurdle for the development of effective relapse prevention therapies. In this study, we used a cocaine+cue self-administration paradigm followed by cue re-exposure to establish that the strength of the drug cue association corresponds to the strength of synapses between the medial geniculate nucleus (MGN) of the thalamus and the lateral amygdala (LA). Furthermore, we demonstrate, via optogenetically induced LTD of MGN-LA synapses, that reversing cocaine-induced potentiation of this pathway is sufficient to inhibit cue-induced relapse-like behavior.

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After retrieval, reactivated memories may destabilize and require restabilization processes to persist, referred to as reconsolidation. The reminder-extinction procedure has been proposed as a behavioral reconsolidation-based intervention to persistently attenuate threat-conditioned memories. After the presentation of a single reminder trial, the conditioned threat memory may enter a labile state, and extinction training during this window can prevent the return of conditioned threat responses. However, findings on this reminder-extinction procedure are mixed and its effectiveness may be subject to boundary conditions, including memory strength. Here, we systematically investigate whether more intense threat memories are less susceptible to disruption through a reminder-extinction procedure. Using a Pavlovian auditory threat conditioning procedure at three different shock intensities, rats acquired conditioned threat responses of variable "strength." Rats subsequently underwent either extinction preceded by a reminder or standard extinction. Although different shock intensities led to different strength threat memories, all groups showed reinstatement of conditioned threat responses irrespective of shock intensity or reminder condition. Hence, regardless of the intensity of the threat memory, the reminder procedure was ineffective in preventing the return of threat responses in rats. We thus find no evidence that threat memory intensity is a potential modulator of the effectiveness of the reminder-extinction procedure. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

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Significance This unique randomized, double-blind, placebo-controlled trial examined the susceptibility to false memories under the influence of cannabis, using a basic (DRM) and two applied (misinformation) paradigms. We used a highly powered experimental design, allowing us to test acute and residual drug effects. To achieve high reproducibility and ecological validity, the misinformation paradigms included an eyewitness and a perpetrator scenario, presented in a virtual-reality environment. We show across different paradigms that cannabis consistently increases susceptibility to false memories. The results have implications for police, legal professionals, and policymakers with regard to the treatment of cannabis-intoxicated witnesses and suspects and the validity of their statements. With the growing global acceptance of cannabis and its widespread use by eyewitnesses and suspects in legal cases, understanding the popular drug’s ramifications for memory is a pressing need. In a double-blind, randomized, placebo-controlled trial, we examined the acute and delayed effects of Δ9-tetrahydrocannabinol (THC) intoxication on susceptibility to false memory in 64 healthy volunteers. Memory was tested immediately (encoding and retrieval under drug influence) and 1 wk later (retrieval sober). We used three different methods (associative word lists and two misinformation tasks using virtual reality). Across all methods, we found evidence for enhanced false-memory effects in intoxicated participants. Specifically, intoxicated participants showed higher false recognition in the associative word-list task both at immediate and delayed test than controls. This yes bias became increasingly strong with decreasing levels of association between studied and test items. In a misinformation task, intoxicated participants were more susceptible to false-memory creation using a virtual-reality eyewitness scenario and virtual-reality perpetrator scenario. False-memory effects were mostly restricted to the acute-intoxication phase. Cannabis seems to increase false-memory proneness, with decreasing strength of association between an event and a test item, as assessed by different false-memory paradigms. Our findings have implications for how and when the police should interview suspects and eyewitnesses.

Systemic administration of drugs that activate the noradrenergic or glucocorticoid system potentiates aversive memory consolidation and reconsolidation. The opposite happens with the stimulation of endocannabinoid signaling under certain conditions. An unbalance of these interacting neurotransmitters can lead to the formation and maintenance of traumatic memories, whose strength and specificity attributes are often maladaptive. Here we aimed to investigate whether originally low-intensity and precise contextual fear memories would turn similar to traumatic ones in rats systemically administered with adrenaline, corticosterone, and/or the cannabinoid type-1 receptor antagonist/inverse agonist AM251 during consolidation or reconsolidation. The high dose of each pharmacological agent evaluated significantly increased freezing times at test in the conditioning context one and nine days later when given alone post-acquisition or post-retrieval. Their respective low dose produced no relative changes when given separately, but co-treatment of adrenaline with corticosterone or AM251 and the three drugs combined, but not corticosterone with AM251, produced results equivalent to those mentioned initially. Neither the high nor the low dose of adrenaline, corticosterone, or AM251 altered freezing times at test in a novel, neutral context two and ten days later. In contrast, animals receiving the association of their low dose exhibited significantly higher freezing times than controls. Together, the results indicate that newly acquired and destabilized threat memory traces become more intense and generalized after a combined interference acting synergistically and mimicking that reported in patients presenting stress-related psychiatric conditions.

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Intra-cranial electroencephalographic brain recordings (iEEG) provide a powerful tool for investigating the neural processes supporting episodic memory encoding and form the basis of experimental therapies aimed at improving memory dysfunction. However, given the invasiveness of iEEG, investigations are constrained to patients with drug-resistant epilepsy for whom such recordings are clinically indicated. Particularly in the case of temporal lobe epilepsy (TLE), neuropathology and the possibility of functional reorganization are potential constraints on the generalizability of intra-cerebral findings and pose challenges to the development of therapies for memory disorders stemming from other etiologies. Here, samples of TLE (N = 16; all of whom had undergone iEEG) and age-matched healthy control (N = 19) participants underwent fMRI as they studied lists of concrete nouns. fMRI BOLDresponses elicited by the study words were segregated according to subsequent performance on tests of delayed free recall and recognition memory. Subsequent memory effects predictive of both successful recall and recognition memory were evident in several neural regions, most prominently in the left inferior frontal gyrus, and did not demonstrate any group differences. Behaviorally, the groups did not differ in overall recall performance or in the strength of temporal contiguity effects. However, group differences in serial position effects and false alarm rates were evident during the free recall and recognition memory tasks, respectively. Despite these behavioral differences, neuropathology associated with temporal lobe epilepsy was apparently insufficient to give rise to detectable differences in the functional neuroanatomy of episodic memory encoding relative to neurologically healthy controls. The findings provide reassurance that iEEG findings derived from experimental paradigms similar to those employed here generalize to the neurotypical population.

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Addiction, the continuous misuse of addictive material, causes long-term dysfunction in the neurological system. It substantially affects the control strength of reward, memory, and motivation. Addictive substances (alcohol, marijuana, caffeine, heroin, methamphetamine (METH), and nicotine) are highly active central nervous stimulants. Addiction leads to severe health issues, including cardiovascular diseases, serious infections, and pulmonary/dental diseases. Drug dependence may result in unfavorable cognitive impairments that can continue during abstinence and negatively influence recovery performance. Although addiction is a critical global health challenge with numerous consequences and complications, currently, there are no efficient options for treating drug addiction, particularly METH. Currently, novel treatment approaches such as psychological contingency management, cognitive behavioral therapy, and motivational enhancement strategies are of great interest. Herein, we evaluate the devastating impacts of different addictive substances/drugs on users′ mental health and the role of tryptophan in alleviating unfavorable side effects. The tryptophan metabolites in the mammalian brain and their potential to treat compulsive abuse of addictive substances are investigated by assessing the functional effects of addictive substances on tryptophan. Future perspectives on developing promising modalities to treat addiction and the role of tryptophan and its metabolites to alleviate drug dependency are discussed.

Reconsolidation is necessary for the restabilization of reactivated memory traces. However, experimental parameters have been suggested as boundary conditions for this process. Here we investigated the role of a spatial memory trace's age, strength, and update on the reconsolidation process in mice. We first found that protein synthesis is necessary for reconsolidation to occur in the hippocampal CA3 region after reactivation of partially acquired and old memories but not for strongly acquired and recent memories. We also demonstrated that the update of a previously stable memory required, again, a memory reconsolidation in the hippocampal CA3. Finally, we found that the reactivation of a strongly acquired memory requires an activation of the anterior cingulate cortex as soon as 24 h after acquisition. This study demonstrates the importance of the knowledge of the task on the dynamic nature of memory reconsolidation processing.

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The discovery in animal research that fear memories may change upon retrieval has sparked a wave of interest into whether this phenomenon of reconsolidation also occurs in humans. The critical conditions under which memory reconsolidation can be observed and targeted in humans, however, remain elusive. Here we report that blocking beta-adrenergic receptors in the brain, either before or after reactivation, effectively neutralizes the expression of fear memory. We show a specific time-window during which beta-adrenergic receptors are involved in the reconsolidation of fear memory. Finally, we observe intact fear memory expression 12 h after reactivation and amnesic drug intake when the retention test takes place during the same day as the intervention, but post-reactivation amnesia after a night of sleep (12 h or 24 h later). We conclude that memory reconsolidation is not simply time-dependent, but that sleep is a final and necessary link to fundamentally change the fear memory engram.Emotional memory can change when retrieved, yet the conditions under which this can occur are not fully described. Here, authors show that taking a pill of propranolol taken during a specific time window can change the expression of fear memory in a person, and that sleep is necessary to forget learned fear.

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Pharmacological targeting of memory reconsolidation is a promising therapeutic strategy for the treatment of fear memory-related disorders. However, the success of reconsolidation-based approaches depends upon the effective destabilisation of the fear memory by memory reactivation. Here, we aimed to determine the functional involvement of dopamine D1 receptors in cued fear memory destabilisation, using systemic drug administration. We observed that direct D1 receptor agonism was not sufficient to stimulate tone fear memory destabilisation to facilitate reconsolidation disruption by the glucocorticoid receptor antagonist mifepristone. Instead, administration of the nootropic nefiracetam did facilitate mifepristone-induced amnesia, in a manner that was dependent upon dopamine D1 receptor activation. Finally, while the combined treatment with nefiracetam and mifepristone did not confer fear-reducing effects under conditions of extinction learning, there was some evidence that mifepristone reduces fear expression irrespective of memory reactivation parameters. The use of combination pharmacological treatment to stimulate memory destabilisation and impair reconsolidation has potential therapeutic benefits, without risking a maladaptive increase of fear.

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A memory trace in its active state is susceptible to interference by amnesic agents, such as hypothermia and electroconvulsive shock, and by NMDA receptor antagonists, suggesting that a time-dependent consolidation process occurs each time a memory is reactivated. The role of β noradrenergic receptors in reconsolidation in rats was examined in both a positively reinforced radial maze task and a footshock-reinforced conditioned emotional response task. For the former, rats were trained over several days in a spatial reference memory task and received a single reactivation trial followed by propranolol. A temporally graded impairment was observed when propranolol treatment occurred after the memory reactivation trial. In the emotional task, memory impairing effects of propranolol were greater when the drug was administered after a reactivation trial than when administered immediately after the initial training. These results suggest that reactivation of memory triggers a β receptor-dependent cascade of intracellular events, recapitulating that which occurs during initial postacquisition consolidation, thus permitting reorganization of the existing memory as a function of new information in the retrieval environment. This remarkable lability of an active memory trace provides a new basis for pharmacotherapeutic intervention in such syndromes as Posttraumatic Stress Disorder. β adrenoreceptor antagonists may be promising pharmacological agents for attenuating debilitating memories at the time of their controlled reactivation.

CF-1 male mice were trained in an inhibitory avoidance (IA) task using either a mild or a high footshock (0.8 or 1.2 mA, 50 Hz, 1 s). A retention test was given 48 h later. Immediately after the retention test, mice were given intra-dorsal hippocampus infusions of either choline (Ch, an α7 nicotinic acetylcholine receptor (α7nAChR) agonist, 0.08-1.30 μg/hippocampus), or methyllycaconitine (MLA, an α7nAChR antagonist, 1.0-30.0 μg/hippocampus). Memory retention was tested again 24 h later. Methyllycaconitine impaired retention performance regardless of footshock intensity and its effects were long lasting. Ch impaired retention performance only in those mice trained with a high footshock. On the contrary, Ch enhanced retention performance when mice were trained with a mild footshock. These effects were long lasting and dose- and time-dependent. Retention performance was not affected in drug-treated mice that were not subjected to memory reactivation, suggesting that the performance effects could not be attributable to non-specific effects of the drugs. Methyllycaconitine effects were dose-dependently reversed by choline, suggesting that MLA and Ch interact at the α7nAChR. Altogether, results suggest that hippocampal α7nAChRs play a critical role in reconsolidation of an IA response in mice, and may also have important implications for dynamic memory processes. This is the first presentation, to our knowledge, indicating that a specific receptor (α7nAChR) is able to modulate consolidated memories after retrieval.

It is widely known that pre-training systemic administration of the muscarinic antagonist scopolamine (SCP) (0.5mg/kg, i.p.) leads to anterograde memory impairment in retention tests. The administration of the α(7)-nicotinic receptor agonist choline (Ch) in the dorsal hippocampus (0.8μg/hippocampus) immediately after memory reactivation allowed recovery from scopolamine-induced memory impairment. This effect of Ch was time-dependent, and retention performance was not affected in drug-treated mice that were not subjected to memory reactivation, suggesting that the performance effects are not due to non-specific effects of the drug. The effects of Ch also depended on the age of the reactivated memory. Altogether, our results suggest that Ch exerts its effects by modulating memory reconsolidation, and that the memory impairment induced by low doses of SCP is a memory expression failure and not a storage deficit. Therefore, reconsolidation, among other functions, might serve to change memory expression in later tests. Summarizing, our results open new avenues about the behavioral significance and the physiological functions of memory reconsolidation, providing new strategies for recovering memories from some types of amnesia.

When subjects are exposed to new learning experiences, the novel information could be acquired and eventually stored through memory consolidation process. The exposure of mice to a novel experience (a hole-board) after being trained in an inhibitory avoidance apparatus is followed by impaired performance of the avoidance memory in subsequent tests. The same impairing effect is produced when mice are exposed to the novel environment after the reactivation of the avoidance memory. This interfering effect is due to impaired consolidation or reconsolidation of the avoidance memory. The administration of the α7-nicotinic receptor agonist choline (Ch) in the dorsal hippocampus (0.8 μg/hippocampus) immediately after the inhibitory avoidance memory reactivation, allowed memory recovery. This effect of Ch was time-dependent, and retention performance was not affected in drug-treated mice that were not subjected to memory reactivation, suggesting that the effects on performance are not due to non-specific effects of the drug. The effects of Ch also depended on the age of the reactivated memory. Altogether, our results suggest that Ch exerts its effects by modulating memory reconsolidation, and that the memory impairment induced by new learning is a memory expression failure and not a storage deficit. Therefore, reconsolidation, among other functions, might serve to change whether a memory will be expressed in later tests. Summarizing, our results open new avenues about the behavioral significance and the physiological functions of memory reconsolidation, providing new strategies for recovering memories from some types of amnesia.

Background Memory updating is essential for integrating new information into existing representations. However, this process could become maladaptive in conditions like post-traumatic stress disorder (PTSD), when fear memories generalize to neutral contexts. Previously, we have shown that contextual fear memory malleability in rats requires activation of M1 muscarinic acetylcholine receptors in the dorsal hippocampus. Here, we investigated the involvement of this mechanism in transfer of contextual fear memories to other contexts using a novel fear memory updating paradigm. Methods Following brief re-exposure to a previously fear conditioned context, male rats (n=8-10/group) were placed into a neutral context to evaluate the transfer of fear memory. We also infused the selective M1 receptor antagonist pirenzepine into the dorsal hippocampus prior to memory reactivation to try to block this effect. Results Results support the hypothesis that fear memory can be updated with novel contextual information, but only if rats are re-exposed to the originally trained context relatively recently prior to the neutral context; evidence for transfer was not seen if the fear memory reactivation was omitted or if it occurred 6h prior to neutral context exposure. The transferred fear persisted for four weeks, and the effect was blocked by M1 antagonism. Conclusions These findings strongly suggest that fear transfer requires reactivation and destabilization of the original fear memory. Specific parameters likely dictate similar generalization in disorders like PTSD. The novel preclinical model introduced here, and its implication of muscarinic receptors in this process, should inform therapeutic strategies in this area.

Hippocampal dopamine D1/D5 receptor-dependent destabilization is necessary for object recognition memory (ORM) updating through reconsolidation. Dopamine also regulates hippocampal theta and gamma oscillations, which are involved in novelty and memory processing. We found that, in adult male rats, ORM recall in the presence of a novel object, but not in the presence of a familiar one, triggers hippocampal theta–gamma coupling. Hippocampal theta–gamma coupling (hPAC) does not happen when ORM destabilization is prevented by blocking D1/D5 receptors, but artificial hPAC generation during recall in the presence of a familiar object enables the amnesic effect of reconsolidation inhibitors. Therefore, hPAC controls ORM destabilization, and its modulation could increase reconsolidation-based psychotherapy efficacy.

The role of sleep in memory consolidation is a widely discussed but still debated area of research. In light of the fact that memory consolidation during sleep is an evolutionary adaptive function, investigating the same phenomenon in nonhuman model species is highly relevant for its understanding. One such species, which has acquired human-analog sociocognitive skills through convergent evolution, is the domestic dog. Family dogs have surfaced as an outstanding animal model in sleep research, and their learning skills (in a social context) are subject to sleep-dependent memory consolidation. These results, however, are correlational, and the next challenge is to establish causality. In the present study, we aimed to adapt a TMR (targeted memory reactivation) paradigm in dogs and investigate its effect on sleep parameters. Dogs (N = 16) learned new commands associated with different locations and afterward took part in a sleep polysomnography recording when they were re-exposed to one of the previously learned commands. The results did not indicate a cueing benefit on choice performance. However, there was evidence for a decrease in choice latency after sleep, while the density (occurrence/minute) of fast sleep spindles was also notably higher during TMR recordings than adaptation recordings from the same animals and even compared with a larger reference sample from a previous work. Our study provides empirical evidence that TMR is feasible with family dogs, even during a daytime nap. Furthermore, the present study highlights several methodological and conceptual challenges for future research.

Learning-activated engram neurons play a critical role in memory recall. An untested hypothesis is that these same neurons play an instructive role in offline memory consolidation. Here we show that a visually-cued fear memory is consolidated during post-conditioning sleep in mice. We then use TRAP (targeted recombination in active populations) to genetically label or optogenetically manipulate primary visual cortex (V1) neurons responsive to the visual cue. Following fear conditioning, mice respond to activation of this visual engram population in a manner similar to visual presentation of fear cues. Cue-responsive neurons are selectively reactivated in V1 during post-conditioning sleep. Mimicking visual engram reactivation optogenetically leads to increased representation of the visual cue in V1. Optogenetic inhibition of the engram population during post-conditioning sleep disrupts consolidation of fear memory. We conclude that selective sleep-associated reactivation of learning-activated sensory populations serves as a necessary instructive mechanism for memory consolidation. Learning-activated engram neurons play a critical role in memory recall but the role of these neurons in offline memory consolidation is unclear. The authors show that sleep-associated reactivation of learning-activated sensory neurons is necessary for memory consolidation.

Upon retrieval, memories can become susceptible to meaningful events, such as stress. Post-retrieval memory changes may be attributed to an alteration of the original memory trace during reactivation-dependent reconsolidation or, alternatively, to the modification of retrieval-related memory traces that impact future remembering. Hence, how post-retrieval memory changes emerge in the human brain is unknown. In a 3-day functional magnetic resonance imaging study, we show that post-retrieval stress impairs subsequent memory depending on the strength of neural reinstatement of the original memory trace during reactivation, driven by the hippocampus and its cross-talk with neocortical representation areas. Comparison of neural patterns during immediate and final memory testing further revealed that successful retrieval was linked to pattern-dissimilarity in controls, suggesting the use of a different trace, whereas stressed participants relied on the original memory representation. These representation changes were again dependent on neocortical reinstatement during reactivation. Our findings show disruptive stress effects on the consolidation of retrieval-related memory traces that support future remembering.

Newly encoded memories are reactivated and consolidated during sleep. However, how the reactivation of a specific memory unfolds over time is poorly understood. What are the temporal dynamics of a single reactivation event within a period of sleep? Does extending a single reactivation opportunity translate to stronger memory benefits? We explored these dynamics by utilizing targeted memory reactivation (TMR), a technique that biases the consolidation of memories via the unobtrusive presentation of memory-associated cues during sleep. Participants learned the on-screen positions of sixty objects, each linked with a unique sound (e.g., cat - meow). Some sounds were then presented during non-REM sleep, with the duration allotted for reactivation causally controlled by varying the timing of the interstimulus interval. TMR did not lead to uniform improvement in memory, and no differences were observed between objects allotted short (2.5 s) and long (7.5 s) reactivation windows. However, memory for objects allotted short windows was impacted by TMR in an encoding-strength-dependent manner, with poorly encoded objects benefiting the most. Classification models trained on EEG data revealed memory reactivation that was time-locked to sound onset during sleep, and this measure of reactivation was linked with memory gains one week later. We did not find evidence for reactivation that extended beyond the time window immediately after sound onset (< 2 s). Although our results are not entirely conclusive, they suggest that the critical processes supporting memory consolidation conclude within < 2 s after reactivation onset and that extended reactivation windows do not confer additional benefits.

Sleep is crucial for memory consolidation, underpinning effective learning. Targeted memory reactivation (TMR) can strengthen neural representations by re-engaging learning circuits during sleep. However, TMR protocols overlook individual differences in learning capacity and memory trace strength, limiting efficacy for difficult-to-recall memories. Here, we present a personalized TMR protocol that adjusts stimulation frequency based on individual retrieval performance and task difficulty during a word-pair memory task. In an experiment comparing personalized TMR, TMR, and control groups, the personalized protocol significantly reduced memory decay and improved error correction under challenging recall. Electroencephalogram (EEG) analyses revealed enhanced synchronization of slow waves and spindles, with a significant positive correlation between behavioral and EEG features for challenging memories. Multivariate classification identified distinct neural signatures linked to the personalized approach, highlighting its ability to target memory-specific circuits. These findings provide novel insights into sleep-dependent memory consolidation and support personalized TMR interventions to optimize learning outcomes.

Abstract Research on memory reconsolidation has been booming in the last two decades, with numerous high-impact publications reporting promising amnestic interventions in rodents and humans. However, our own recently-published failed replication attempts of reactivation-dependent amnesia for fear memories in rats suggest that such amnestic effects are not always readily found and that they depend on subtle and possibly uncontrollable parameters. The discrepancy between our observations and published studies in rodents suggests that the literature in this field might be biased. The aim of the current study was to gauge the presence of publication bias in a well-delineated part of the reconsolidation literature. To this end, we performed a systematic review of the literature on reactivation-dependent amnesia for contextual fear memories in rodents, followed by a statistical assessment of publication bias in this sample. In addition, relevant researchers were contacted for unpublished results, which were included in the current analyses. The obtained results support the presence of publication bias, suggesting that the literature provides an overly optimistic overall estimate of the size and reproducibility of amnestic effects. Reactivation-dependent amnesia for contextual fear memories in rodents is thus less robust than what is projected by the literature. The moderate success of clinical studies may be in line with this conclusion, rather than reflecting translational issues. For the field to evolve, replication and non-biased publication of obtained results are essential. A set of tools that can create opportunities to increase transparency, reproducibility and credibility of research findings is provided.

ABSTRACT It is well established that newly acquired information is stabilized over time by processes underlying memory consolidation, these events can be impaired by many drug treatments administered shortly after learning. The consolidation hypothesis has been challenged by a memory integration hypothesis, which suggests that the processes underlying new memories are vulnerable to incorporation of the neurobiological alterations induced by amnesic drugs generating a state‐dependent memory. The present experiments investigated the effects of amnesic drugs infused into the insular cortex of male Wistar rats on memory for object recognition training. The findings provide evidence that infusions of several amnesic agents including a protein synthesis inhibitor, an RNA synthesis inhibitor, or an NMDA receptor antagonist administered both after a specific period of time and before retrieval induce state‐dependent recognition memory. Additionally, when amnesic drugs were infused outside the early consolidation window, there was amnesia, but the amnesia was not state‐dependent. Data suggest that amnesic agents can induce state‐dependent memory when administered during the early consolidation window and only if the duration of the drug effect is long enough to become integrated to the memory trace. In consequence, there are boundary conditions in order to induce state‐dependent memory. HIGHLIGHTSAnisomycin induces state‐dependent recognition memory.DRB, an elongation RNA inhibitor, induces state‐dependent recognition memory.The duration of drug action is a boundary condition for the induction of state‐dependent recognition memory.Drugs induce state‐dependent memory only when infused at early consolidation window.

A growing body of evidence suggests that sleep can help to decouple the memory of emotional experiences from their associated affective charge. This process is thought to rely on the spontaneous reactivation of emotional memories during sleep, though it is still unclear which sleep stage is optimal for such reactivation. We examined this question by explicitly manipulating memory reactivation in both rapid-eye movement sleep (REM) and slow-wave sleep (SWS) using targeted memory reactivation (TMR) and testing the impact of this manipulation on habituation of subjective arousal responses across a night. Our results show that TMR during REM, but not SWS significantly decreased subjective arousal, and this effect is driven by the more negative stimuli. These results support one aspect of the sleep to forget, sleep to remember (SFSR) hypothesis which proposes that emotional memory reactivation during REM sleep underlies sleep-dependent habituation. Hutchison et al. played sounds, which were paired with either emotionally negative or neutral images, to participants during either REM or slow-wave stages of sleep. They demonstrated that such targeted memory reactivation during REM sleep, but not slow-wave sleep, significantly decreased arousal. This provides key information about memory consolidation/loss during sleep.

Although reconsolidation-based interventions constitute a promising new avenue to treating fear and anxieties disorders, the success of the intervention is not guaranteed. The initiation of memory reconsolidation is dependent on whether a mismatch between the experienced and predicted outcome-a prediction error (PE)-occurs during fear memory reactivation. It remains, however, elusive whether any type of PE renders fear memories susceptible to reconsolidation disruption. Here, we investigated whether a value PE, elicited by an outcome that is better or worse than expected, is necessary to make fear memories susceptible to reconsolidation disruption or whether a model-based identity PE, i.e., a PE elicited by an outcome equally aversive but different than expected, would be sufficient. Blocking beta-adrenergic receptors with propranolol HCl after reactivation did, however, not reduce the expression of fear after either type of PE. Instead, we observed intact fear memory expression 24 h after reactivation in the value-, identity- and a no-PE control group. The present results do not corroborate our earlier findings of reconsolidation disruption and point towards challenges that the field is currently facing in observing evidence for memory reconsolidation at all. We provide potential explanations for the unexpected failure of replicating reconsolidation disruption and discuss future directions.

Animals consolidate some, but not all, learning experiences into long-term memory. Across the animal kingdom, sleep has been found to have a beneficial effect on the consolidation of recently formed memories into long-term storage. However, the underlying mechanisms of sleep dependent memory consolidation are poorly understood. Here, we show that consolidation of courtship long-term memory in Drosophila is mediated by reactivation during sleep of dopaminergic neurons that were earlier involved in memory acquisition. We identify specific fan-shaped body neurons that induce sleep after the learning experience and activate dopaminergic neurons for memory consolidation. Thus, we provide a direct link between sleep, neuronal reactivation of dopaminergic neurons, and memory consolidation.

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In conditioned odor aversion (COA), the association of a tasteless odorized solution (the conditioned stimulus [CS]) with an intraperitoneal injection of LiCl (the unconditioned stimulus [US[), which produces visceral malaise, results in its future avoidance. The strength of this associative memory is mainly dependent on two parameters, that is, the strength of the US and the interstimuli interval (ISI). In rats, COA has been observed only with ISIs of ≤15 min and LiCl (0.15 M) doses of 2.0% of bodyweight, when tested 48 h after acquisition (long-term memory [LTM]). However, we previously reported a robust aversion in rats trained with ISIs up to 60 min when tested 4 h after acquisition (short-term memory [STM]). Since memories get reactivated during retrieval, in the current study we hypothesized that testing for STM would reactivate this COA trace, strengthening its LTM. For this, we compared the LTM of rats trained with long ISIs or low doses of LiCl initially tested for STM with that of rats tested for LTM only. Interestingly, rats conditioned under parameters sufficient to produce STM, but not LTM, showed a reliable LTM when first tested for STM. These observations suggest that under suboptimal training conditions, such as long ISIs or low US intensities, a CS–US association is established but requires reactivation in the short-term in order to persist in the long-term.

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There is an ongoing need to identify novel pharmacological agents for the effective treatment of depression. One emerging candidate, which has demonstrated rapid-acting antidepressant effects in treatment-resistant groups, is nitrous oxide (N2O)—a gas commonly used for sedation and pain management in clinical settings and with a range of pharmacological effects, including antagonism of NMDA glutamate receptors. A growing body of evidence suggests that subanaesthetic doses of N2O (50%) can interfere with the reconsolidation of maladaptive memories in healthy participants and across a range of disorders. Negative biases in memory play a key role in the onset, maintenance, and recurrence of depressive episodes, and the disruption of affective memory reconsolidation is one plausible mechanism through which N2O exerts its therapeutic effects. Understanding N2O’s mechanisms of action may facilitate future treatment development in depression. In this narrative review, we introduce the evidence supporting an antidepressant profile of N2O and evaluate its clinical use compared to other treatments. With a focus on the specific memory processes that are thought to be disrupted in depression, we consider the effects of N2O on memory reconsolidation and propose a memory-based mechanism of N2O antidepressant action.

Retrieval can bring memories to a labile state, creating a window to modify its content during reconsolidation. Numerous studies have investigated this period to elucidate reconsolidation mechanisms, understand long-term memory persistence, and develop therapeutic strategies for memory-related psychiatric disorders. However, the temporal dynamics of post-retrieval memory processes have been largely overlooked, leading to mixed findings and hindering the development of targeted interventions. This review discusses retrieval-related cellular and molecular events and how they develop in series and parallel across time. Emerging evidence suggests that some mechanisms triggered after fear memory retrieval can influence either reconsolidation or persistence in different time windows. The temporal boundaries of these post-retrieval processes are still unclear. Further research integrating behavioral and molecular approaches to a deeper understanding of reconsolidation and persistence temporal dynamics is essential to address current debates, including which system/pathway offers the most effective therapeutic window of opportunity.

Anxiety disorders can be effectively treated with both cognitive behavioural therapy and psychopharmacological interventions. However, only 50% of patients demonstrate significant benefits from these approaches. Therefore, investigating strategies to improve treatment effectiveness or develop novel therapeutic approaches remains an important research objective. Current therapeutic modalities may leave the original fear memory intact, potentially leading to symptom recurrence over time. In contrast, the disruption of reconsolidation processes can facilitate permanent modifications to fear memory, resulting in a reduced risk of relapse after psychotherapy. Recent laboratory studies have shown that the reconsolidation of experimentally induced fear can be effectively disrupted by repetitive transcranial magnetic stimulation (rTMS) and significantly prevents the return of fear. In this study, we translated these results to participants with elevated fear of spiders. 34 participants with spider fear were randomly assigned to a verum or a placebo intervention using continuous theta-burst stimulation (80% of resting motor threshold) applied over the right dorsolateral prefrontal cortex ten minutes after the reactivation (3minute confrontation with a living tarantula) of the spider fear memory. The ANOVA for the primary outcome (Spider Phobia Questionnaire, SPQ) resulted in a significant effect of time, but no significant interaction of time and treatment group. Notably, exploratory analyses revealed a significant correlation between stimulation intensity in the verum group and the reduction in spider fear. This association suggest that rTMS-induced disruptions of reconsolidation may serve as a viable therapeutic option for anxiety disorders; however, further research is needed to delineate the optimal parameters for such interventions.

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Esketamine, the right-handed optical isomer of racemic ketamine, is a rapidly acting antidepressant approved by the FDA for treatment-resistant depression in 2019. However, few studies have investigated esketamine's role in learning and memory, particularly in the context of memory reconsolidation. Herein, we evaluated esketamine's role in memory reconsolidation in 7-week-old male Institute of Cancer Research mice subjected to the novel object recognition (NOR) memory task. The NOR reconsolidation procedure comprised three phases: sampling, reactivation, and testing. Esketamine-enhanced NOR memory performance when injected into mice 0 h after reactivation rather than following a 6 h delay. Conversely, administering esketamine 24 h after sampling without reactivation did not enhance NOR memory performance. Notably, esketamine exhibited no discernible effects on nonspecific responses, such as locomotor activity and exploratory behavior. Furthermore, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor antagonist NBQX effectively blocked the esketamine-induced enhancement of memory reconsolidation. In conclusion, esketamine treatment markedly improves memory reconsolidation in NOR tasks, and this effect is linked to AMPA receptor activity.

The gold standard of scientific medicine is using knowledge of underlying processes to shape treatment. This has previously not been possible for psychotherapy, but with the science of memory reconsolidation, requirements for change can be more precisely defined and can improve psychotherapeutic technique by focusing on three areas: the activation of maladaptive implicit learning, the provision of disconfirming information, and attention to transmission between consciousness and limbic memory. Overall, better understanding of processes helps liberate psychotherapy from rigidities dictated by set methods.

Since its rediscovery at the beginning of the 21^st Century, memory reconsolidation has been proposed to be a therapeutic target for reducing the impact of emotional memories that can go awry in mental health disorders such as drug addiction (substance use disorder, SUD). Addiction can be conceptualised as a disorder of learning and memory, in which both pavlovian and instrumental learning systems become hijacked into supporting drug-seeking and drug-taking behaviours. The past two decades of research have characterised the details of the molecular pathways supporting the reconsolidation of pavlovian cue-drug memories, with more recent work indicating that the reconsolidation of instrumental drug-seeking memories also relies upon similar mechanisms. This narrative review considers what is known about the mechanisms underlying the reconsolidation of pavlovian and instrumental memories associated with drug use, how these approaches have translated to experimental medicine studies, and the challenges and opportunities for the clinical use of reconsolidation-based therapies.

The mechanistic target of rapamycin (mTOR) kinase is known to mediate the formation and persistence of aversive memories. Rapamycin, an mTOR inhibitor, administered around the time of reactivation blocks retrieval-induced mTOR activity and de novo protein synthesis in the brains of rodents, while correspondingly diminishing subsequent fear memory. The goal of the current experiments was to further explore rapamycin's effects on fear memory persistence. First, we examined whether mTOR blockade at different time-points after reactivation attenuates subsequent contextual fear memory. We show that rapamycin treatment 3 or 12hours post-reactivation disrupts memory persistence. Second, we examined whether consecutive days of reactivation paired with rapamycin had additive effects over a single pairing at disrupting a contextual fear memory. We show that additional reactivation-rapamycin pairings exacerbates the reconsolidation impairment. Finally, we examined if impaired reconsolidation of a contextual fear memory from rapamycin treatment had any after-effects on learning and recalling a new fear association. We show that rapamycin-impaired reconsolidation does not affect new learning or recall and protects against fear generalization. Our findings improve our understanding of mTOR- dependent fear memory processes, as well as provide insight into potentially novel treatment options for stress-related psychopathologies such as posttraumatic stress disorder.

RATIONALE Fear memory, a fundamental symptom of post-traumatic stress disorder (PTSD), is improved by (2R, 6R)-hydroxynorketamine ((2R, 6R)-HNK) administration. However, the phase of fear memory in which the injected drug is the most effective at mitigating PTSD-like effects remains unknown. OBJECTIVE This study aimed to explore the effects of (2R, 6R)-HNK administration during three phases [acquisition (AP), reconsolidation (RP), and extinction (EP)] on PTSD-like behaviors in single prolonged stress (SPS) and contextual fear conditioning (CFC) rat models. The effects of VGF-inducible type of nerve growth factor (VGF), brain-derived neurotrophic factor (BDNF), and GluA1 on hippocampus (HIP) expression were also explored. METHODS SPS and CFC (SPSC) were used to establish a PTSD rat model. After lateral ventricle injection of 5μL (2R, 6R)-HNK (0.5 nmol). Anxiety-depression-like behaviors were assessed in rats by the open field test (OFT) and elevated plus maze test (EPMT). Situational fear responses were evaluated in rodents by freezing behavior test (FBT) test. In addition, GluA1, VGF, and BDNF were assessed in the hippocampus by Western blot assay (WB) and Immunohistochemistry assay (IF). RESULTS SPSC procedure induced PTSD-like behaviors. The SPSC group had decreased spontaneous exploratory behavior and increased fear response. The (2R, 6R)-HNK group showed improved SPSC-induced reduction in GluA1, VGF, and BDNF levels in the HIP. During RP, anxiety and fear avoidance behaviors were alleviated, and the protein levels of GluA1, VGF, and BDNF in the HIP were restored. In contrast, no significant improvement was noted during AP and EP. CONCLUSIONS (2R,6R)-HNK modulates the VGF/BDNF/GluA1 signaling pathway in the hippocampus and improves PTSD-like behaviors during the reconsolidation phase of fear memory in rats, which may provide a new target for the clinical treatment and prevention of fear-related disorders such as PTSD.

Reconsolidation turns memories into a responsive state that allows their modulation until they stabilize again. This phenomenon attracted remarkable attention due to its potential impact on therapeutics and education. Recent evidence revealed that different memories undergo reconsolidation via a behavioral tagging process. Thus, their re-stabilization involves setting “reconsolidation-tags” and synthesizing plasticity-related proteins for their capture at the tagged sites. Here, we studied the possibility of affecting these fundamental mechanisms to modulate reconsolidation. Our findings, in laboratory rats, indicate that exploring a novel environment 60 min before or after memory reactivation improves spatial object recognition memory by promoting protein synthesis. Conversely, experiencing novelty immediately after reactivation impairs the reconsolidation by affecting the tags. Similar effects, but with a different optimal time window for improvement, occur in inhibitory avoidance memory. These results highlight the possibility of modulating existing memories using non-invasive interventions that selectively affect the fundamental mechanisms of behavioral tagging during their reconsolidation. A study on rats shows how to modulate memories by associating their recall with non-invasive behavioral experiences: timing defines the nature of change acting on the key mechanisms of the behavioral tagging process underlying memory reconsolidation.

Targeting reconsolidation with propranolol, a blocker of β-adrenergic receptors (β-ARs), emerged as a potential treatment for maladaptive memories such as those involved in posttraumatic stress disorder (PTSD). Reconsolidation targeting treatments for PTSD are becoming a common practice in the clinic and it is important to unveil any side effects upon 'non-targeted' memories. While previous studies have focused on propranolol's effects on the reconsolidation of emotional/distressful memories, the present study asked whether propranolol is involved in the reconsolidation of recognition memories - by assessing its effects on distinct memory components and the role of the dorsal hippocampus. Rats performed an object recognition (OR) task where they were exposed to different objects: A and B presented during the sample phase; A and C presented during the reactivation phase; and D in combination of either A, B, or C during a final test. Intra-hippocampal injections of propranolol (5 µg or 10 µg) were conducted immediately after the reactivation session. Propranolol infusions consistently impaired the addition of novel information to the previously consolidated memory trace regardless of dose, and the retention of familiar objects was not affected. Higher doses of propranolol also hindered memory of a familiar object that was not presented during the reactivation session, but was previously placed at the same location where novel information was presented during reactivation. The present results shed light on the role of β-ARs on the reconsolidation of different memory components and argue for the need for further studies examining possible recognition memory deficits following propranolol treatment.

Background Reconsolidation impairment using propranolol is a novel intervention for mental disorders with an emotional memory at their core. In this systematic review and meta-analysis, we examined the evidence for this intervention in healthy and clinical adult samples. Methods We searched 8 databases for randomized, double-blind studies that involved at least 1 propranolol group and 1 placebo group. We conducted a meta-analysis of 14 studies (n = 478) in healthy adults and 12 studies in clinical samples (n = 446). Results Compared to placebo, reconsolidation impairment under propranolol resulted in reduced recall of aversive material and cue-elicited conditioned emotional responses in healthy adults, as evidenced by an effect size (Hedges g) of −0.51 (p = 0.002, 2-tailed). Moreover, compared to placebo, reconsolidation impairment under propranolol alleviated psychiatric symptoms and reduced cue-elicited reactivity in clinical samples with posttraumatic stress disorder, addiction or phobia (g = −0.42, p = 0.010). Limitations Methodological differences between studies posed an obstacle for identifying sources of heterogeneity. Conclusion Reconsolidation impairment is a robust, well-replicated phenomenon in humans. Its clinical use is promising and deserves further controlled investigation.

Memory retrieval is not a passive process. When a memory is retrieved, it returns to a labile state and undergoes reconsolidation to be re-stored. The discovery of this memory reconsolidation has had a major impact on memory consolidation theory. In other words, it suggested that memory is more dynamic than expected and can be modified through reconsolidation. Conversely, a conditioned fear memory undergoes memory extinction after retrieval, and it is thought that extinction does not reflect its erasure, but rather new inhibitory learning of the original conditioned memory. We have investigated the relationship between memory reconsolidation and extinction by comparing their behavioral, cellular, and molecular mechanisms. Memory reconsolidation and extinction have opposite functions on contextual fear and inhibitory avoidance memories; reconsolidation maintains or strengthens fear memory, whereas extinction weakens it. Importantly, reconsolidation and extinction are contrasting memory processes not only at the behavioral level but also at cellular and molecular levels. Furthermore, our analysis revealed that reconsolidation and extinction are not independent processes, but interact with each other. Interestingly, we also found a "memory transition process" that switches the fear memory process from reconsolidation to extinction after retrieval. Investigating the mechanisms of reconsolidation and extinction will contribute to our understanding of the dynamic nature of memory.

Disrupting memory reconsolidation provides an opportunity to abruptly reduce the behavioural expression of fear memories with long-lasting effects. The success of a reconsolidation intervention is, however, not guaranteed as it strongly depends on the destabilization of the memory. Identifying the necessary conditions to trigger destabilization remains one of the critical challenges in the field. We aimed to replicate a study from our lab, showing that the occurrence of a prediction error (PE) during reactivation is necessary but not sufficient for destabilization. We tested the effectiveness of a reactivation procedure consisting of a single PE, compared to two control groups receiving no or multiple PEs. All participants received propranolol immediately after reactivation and were tested for fear retention 24 h later. In contrast to the original results, we found no evidence for a reconsolidation effect in the single PE group, but a straightforward interpretation of these results is complicated by the lack of differential fear retention in the control groups. Our results corroborate other failed reconsolidation studies and exemplify the complexity of experimentally investigating this process in humans. Thorough investigation of the interaction between learning and memory reactivation is essential to understand the inconsistencies in the literature and to improve reconsolidation interventions.

No abstract available

Posttraumatic nightmares may exacerbate and perpetuate the daytime symptoms of posttraumatic stress disorder and might represent a therapeutic target. The therapeutic strategy of memory reconsolidation using the β-adrenergic receptor blocker propranolol associated with re-exposure psychotherapy is a promising treatment in patients with posttraumatic stress disorder. Previous studies have established this therapy is effective in reducing overall clinician-assessed posttraumatic stress disorder symptoms, but to date no previous study has specifically focused on posttraumatic nightmares in this therapy. This study provides a preliminary assessment of the evolution of nightmare severity during this therapy protocol compared with the decrease of the other posttraumatic stress disorder symptoms. It evaluates the incidence of side effects and examines the relative effects on posttraumatic nightmares. Patients were recruited as part of the Paris Mémoire Vive Study. Data were collected using a prospective longitudinal design including 1 baseline visit, 6 therapeutic visits, and 2 follow-up visits. During the 6 therapeutic visits, propranolol was administered orally 60 to 75 minutes prior to the psychotherapeutic session. On average, nightmare severity decreased from “severe” to “mild” during the protocol and remained stable 2 months after the last session. Whereas 85% of patients reported nightmares at baseline, only 50% still had them after the protocol. The protocol was generally well tolerated and did not increase nightmare severity for any patient in the study. Memory reconsolidation therapy with propranolol seems promising in reducing nightmare severity, up to and including remission. However, research using a randomized controlled design and assessing maintenance of nightmare extinction is warranted. Registry: ClinicalTrials.gov; Name: Using Reconsolidation Blockade to Treat Trauma Related Disorders After Paris Attacks: An Effectiveness Study (PARIS-MEM); Identifier: NCT02789982; URL: https://www.clinicaltrials.gov/ct2/show/NCT02789982. Mallet C, Chick CF, Maatoug R, Fossati P, Brunet A, Millet B. Memory reconsolidation impairment using the β-adrenergic receptor blocker propranolol reduces nightmare severity in patients with posttraumatic stress disorder: a preliminary study. J Clin Sleep Med. 2022;18(7):1847–1855.

Background Memory impairment is among one of the greatest cognitive complaints in midlife and in old age. Considering the importance of good memory functioning in everyday life, it is crucial to study interventions that can reduce the natural decline in this cognitive function. Transcranial Magnetic Stimulation (TMS) studies have demonstrated that the lateral prefrontal cortex (PFC) plays a causal role in enhancing episodic memory recall through reconsolidation. Using a similar paradigm with transcranial direct current stimulation (tDCS) over the left lateral PFC, facilitation effects were observed in delayed memory retrieval in older adults with subjective memory complaints (SMCs) and amnestic Mild Cognitive Impairment (aMCI). However, it remains unclear which potential factors (i.e., tDCS group, cognitive reserve, education level, diagnosis and encoding performance) directly and/or indirectly modulate the tDCS-induced memory reconsolidation effects. Methods We reanalyzed data acquired in our previous tDCS studies with 22 SMC and 18 aMCI participants from the perspective of predicting delayed memory retrieval performance. These studies included a learning session on Day 1, a reactivation by a contextual reminder followed by 15 min of tDCS session on Day 2 (24 h after Day 1), and two retrieval sessions (free recall and recognition) tested on Days 3 and 30 (48 h and 30 Days after Day 1). Results Univariate models showed that tDCS group (sham vs. active) significantly predicted memory recognition (but not free recall), evidenced by higher scores in the active tDCS group than in sham group, confirming our previous results. Encoding performance and diagnosis (SMC vs. aMCI) significantly predicted memory retrieval, suggesting higher performances in individuals with SMC than in those with aMCI. Regarding cognitive reserve, higher leisure time activity subscores significantly predicted better memory recognition. Finally, multiple models did not show any tDCS group × predictor interaction effects, indicating that the effects of the predictors on retrieval occurred irrespective of tDCS group. Conclusion Our results shed light on predicting factors of episodic memory retrieval in this reconsolidation paradigm in individuals with SMC and aMCI. The findings suggest that multifactorial interventions program may be most promising to slow cognitive decline and delay the onset of dementia.

Erasing maladaptive memories has been a challenge for years. A way to change fear memories is to target the process of reconsolidation, during which a retrieved memory transiently returns to a labile state, amenable to modification [1, 2]. Disruption of human fear-memory reconsolidation has been classically attempted with pharmacological [3] or behavioral (e.g., extinction) [4] treatments that, however, do not clarify the underlying brain mechanism. To address this issue, in 84 healthy humans submitted to six experiments, here, we combined a differential fear conditioning paradigm with repetitive transcranial magnetic stimulation (rTMS) administered in a state-dependent manner. In a critical condition, we stimulated the dorsolateral prefrontal cortex (dlPFC) 10 min after a reminder cue that reactivated a fear memory acquired 1 day before. At testing, 24 h after rTMS, participants exhibited decreased physiological expression of fear, as shown by their skin conductance response. Similar reductions were observed when targeting the left and the right dlPFC. In contrast, no decrease was observed in participants tested immediately after dlPFC-rTMS or in participants receiving either control rTMS (i.e., active control site and sham stimulations) or dlPFC-rTMS without preceding fear-memory reactivation, thus showing both the site and time specificity and state dependency of our rTMS intervention. Expression of fear was indeed reduced only when dlPFC-rTMS was administered within the reconsolidation time window. Moreover, dlPFC-rTMS prevented subsequent return of fear after extinction training. These findings highlight the causal role of dlPFC in fear-memory reconsolidation and suggest that rTMS can be used in humans to prevent the return of fear.

Awake quiescence immediately after encoding is conducive to episodic memory consolidation. Retrieval can render episodic memories labile again, but reconsolidation can modify and restrengthen them. It remained unknown whether awake quiescence after retrieval supports episodic memory reconsolidation. We sought to examine this question via an object-location memory paradigm. We failed to probe the effect of quiescence on reconsolidation, but we did observe an unforeseen “delayed” effect of quiescence on consolidation. Our findings reveal that the beneficial effect of quiescence on episodic memory consolidation is not restricted to immediately following encoding but can be achieved at a delayed stage and even following a period of task engagement.

Memory reconsolidation is a fundamental plasticity process in the brain that allows established memories to be changed or erased. However, certain boundary conditions limit the parameters under which memories can be made plastic. Strong memories do not destabilize, for instance, although why they are resilient is mostly unknown. Here, we extend the understanding of the mechanisms implicated in reconsolidation-resistant memories by investigating the hypothesis that specific modulatory signals shape memory formation into a state that lacks lability. We find that the activation of the noradrenaline-locus coeruleus system (NOR-LC) during strong fear memory encoding increases molecular mechanisms of stability at the expense of lability in the amygdala. Preventing the NOR-LC from modulating strong fear encoding results in the formation of memories that can undergo reconsolidation within the amygdala and thus are vulnerable to post-reactivation interference. Thus, the memory strength boundary condition on reconsolidation is set at the time of encoding by the action of the NOR-LC.

Researchers have suggested that psychotherapy may be enhanced by the addition of 3,4‐methylenedioxymethamphetamine (MDMA), particularly in the treatment of disorders wherein interpersonal dysfunction is central, such as social anxiety disorder. We review literature pertaining to three potential processes of change that may be instigated during sessions involving MDMA administration in the treatment of social anxiety disorder.

ABSTRACT MDMA‐assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA‐assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear‐ and anxiety‐related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD. HIGHLIGHTSMDMA‐assisted psychotherapy for treatment of posttraumatic stress disorder received Breakthrough Therapy designation by FDA after six Phase 2 trials demonstrated promising safety and efficacy results.MDMA stimulates release of monoamines, hormones, and signaling molecules that modulate emotional memory circuits engaged in reprocessing of traumatic memories.Fear extinction and memory reconsolidation could possibly be mechanisms underlying the beneficial outcomes of MDMA‐assisted psychotherapy for reducing PTSD symptoms.

Research in nonhuman animals suggests that reactivation can induce a transient, unstable state in a previously consolidated memory, during which the memory can be disrupted or modified, necessitating a process of restabilization in order to persist. Such findings have sparked a wave of interest into whether this phenomenon, known as reconsolidation, occurs in humans. Translating research from animal models to human experiments and even to clinical interventions is an exciting prospect, but amid this excitement, relatively little work has critically evaluated and synthesized existing research regarding human memory reconsolidation. In this review, we formalize a framework for evaluating and designing studies aiming to demonstrate human memory reconsolidation. We use this framework to shed light on reconsolidation-based research in human procedural memory, aversive and appetitive memory, and declarative memory, covering a diverse selection of the most prominent examples of this research, including studies of memory updating, retrieval-extinction procedures, and pharmacological interventions such as propranolol. Across different types of memory and procedure, there is a wealth of observations consistent with reconsolidation. Moreover, some experimental findings are already being translated into clinically relevant interventions. However, there are a number of inconsistent findings, and the presence of alternative explanations means that we cannot conclusively infer the presence of reconsolidation at the neurobiological level from current evidence. Reconsolidation remains a viable but hotly contested explanation for some observed changes in memory expression in both humans and animals. Developing effective and efficient new reconsolidation-based treatments can be a goal that unites researchers and guides future experiments.

The processes of memory formation and its storage are extremely dynamic. Therefore, the determination of the nature and temporal evolution of the changes that underlie the molecular mechanisms of retrieval and cause reconsolidation of memory is the key to understanding memory formation. Retrieval induces the plasticity, which may result in reconsolidation of the original memory and needs critical molecular events to stabilize the memory or its extinction. 4-Chloro-DL-phenylalanine (P-chlorophenylalanine-PCPA) depresses the most limiting enzyme of serotonin synthesis the tryptophan hydroxylase. It is known that PCPA reduces the serotonin content in the brain up to 10 times in rats (see Methods). We hypothesized that the PCPA could behave the similar way in snails and could reduce the content of serotonin in snails. Therefore, we investigated the effect of PCPA injection on contextual memory reconsolidation using a protein synthesis blocker in snails after training according to two protocols of different intensities. The results obtained in training according to the first protocol using five electrical stimuli per day for 5 days showed that reminding the training environment against the background of injection of PCPA led to a significant decrease in contextual memory. At the same time, the results obtained in training according to the second protocol using three electrical stimuli per day for 5 days showed that reminding the training environment against the injection of PCPA did not result in a significant change in contextual memory. The obtain results allowed us to conclude that the mechanisms of processes developed during the reconsolidation of contextual memory after a reminding depend both on the intensity of learning and on the state of the serotonergic system.

Addiction can be conceptualised as a disorder of maladaptive learning and memory. Therefore, maladaptive drug memories supporting drug-seeking and relapse behaviours may present novel treatment targets for therapeutic approaches based upon reconsolidation-blockade. It is known that different structures within the limbic corticostriatal system contribute differentially to different types of maladaptive drug memories, including pavlovian associations between environmental cues and contexts with the drug high, and instrumental memories underlying drug-seeking. Here, we review the mechanisms underlying drug memory reconsolidation in the amygdala, striatum, and hippocampus, noting similarities and differences, and opportunities for future research.

No abstract available

Currently, there are no approved pharmacotherapies for addiction to cocaine and other psychostimulant drugs. Several studies have proposed that cannabidiol (CBD) could be a promising treatment for substance use disorders. In the present work, the authors describe the scarce preclinical and human research about the actions of CBD on the effects of stimulant drugs, mainly cocaine and methamphetamine (METH). Additionally, the possible mechanisms underlying the therapeutic potential of CBD on stimulant use disorders are reviewed. CBD has reversed toxicity and seizures induced by cocaine, behavioural sensitization induced by amphetamines, motivation to self-administer cocaine and METH, context- and stress-induced reinstatement of cocaine and priming-induced reinstatement of METH seeking behaviours. CBD also potentiated the extinction of cocaine- and amphetamine-induced conditioned place preference (CPP), impaired the reconsolidation of cocaine CPP and prevented priming-induced reinstatement of METH CPP. Observational studies suggest that CBD may reduce problems related with crack-cocaine addiction, such as withdrawal symptoms, craving, impulsivity and paranoia (Fischer et al., 2015). The potential mechanisms involved in the protective effects of CBD on addiction to psychostimulant drugs include the prevention of drug-induced neuroadaptations (neurotransmitter and intracellular signalling pathways changes), the erasure of aberrant drug-memories, the reversion of cognitive deficits induced by psychostimulant drugs and the alleviation of mental disorders comorbid with psychostimulant abuse. Further, preclinical studies and future clinical trials are necessary to fully evaluate the potential of CBD as an intervention for cocaine and methamphetamine addictive disorders.

Background: Cocaine may cause persistent changes in the brain, which are more apparent in DA transporter (DAT) and DA receptor availability within the nucleus accumbens (NAc). On the other hand, the DA D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for substance use disorders. Aims: This study aims to assess the impact of selective D3R antagonism on DAT and D3R after reinstatement of cocaine preference (CPP) induced by an acute session of social defeat stress (SDS) and a cocaine prime in mice after a period of abstinence. Methods: Male mice were conditioned with 25 mg/kg of cocaine for 4 days. After 60 days of extinction training mice were pretreated with the selective D3R antagonist SB-277011A before the re-exposure to a priming dose of cocaine or to a single SDS session. CPP scores were determined and levels of DAT, D3R, phospho Akt (pAkt) and phospho mTOR (pmTOR) were assessed in the NAc shell. Results: An increase in DAT and D3R expression was seen in the NAc after both a cocaine prime- and SDS-induced reinstatement of CPP. Pretreatment with SB-277011A blocked elevated DAT and D3R expression as well as SDS-induced reinstatement. By contrast, the blockade of D3R did not modified the cocaine prime-induced CPP. Changes in DAT and D3R expression do not seem to occur via the canonic pathway involving Akt/mTOR. Conclusions: Our results suggest that the selective D3R antagonist ability to inhibit DAT and D3R up-regulation could represent a possible mechanism for its behavioral effects in cocaine-memories reinstatement induced by social stress.

No abstract available

Cocaine-induced neuroinflammation plays an important role in the pathophysiology of drug addiction. Evidence suggests that the immune response contributes for memory consolidation related to place preference behavior underlying cocaine administration in mice. Conditioned place preference (CPP) is a protocol extensively used to study the rewarding and/or aversive motivational effects of drug abuse in rodents, reproducing cocaine-seeking behavior in humans. Besides the variety of apparatus used in the CPP protocol, whether different types of apparatus are able to induce the same conditioned behavior response and neurobiological changes remains to be fully explored. We hypothesize that the immune response is involved in the cocaine-induced CPP and that the type of apparatus might influence this response. Herein, two- and three-compartment apparatuses were tested using the behavioral model of CPP. Cocaine-induced CPP was demonstrated in both apparatuses. However, mice injected with cocaine had decreased levels of IL-1β, IL-6, IL-10, and GDNF in the pre-frontal cortex, and decreased CX3CL1 in the striatum, in the CPP protocol using three compartments compared to controls. While similar levels were seen in the CPP protocol using two compartments. In conclusion, the current study demonstrated that the type of apparatus might influence the investigation of neurobiological mechanisms associated with cocaine-induced CPP. Our data also suggest that the three compartment-apparatus seems to be a more appropriate model to investigate the neuroinflammatory response related to cocaine addiction.

No abstract available

Conditioned place preference (CPP) is a widely used method to assess the rewarding effects of drug and non-drug stimuli. This paradigm has been successfully demonstrated across several species, although rats seem to be the most prevalent model. Given the significant neurophysiological discrepancies between rodents and humans, as well as the technical and ethical limitations of research involving the latter, CPP protocols employing nonhuman primates (NHPs) have been reported in the past 25 years. In this review, we examined the literature on CPP studies using NHPs, including a variety of unconditioned stimuli. A total of 14 studies, involving macaques or marmosets, met the inclusion criteria. Overall, findings indicate that CPP effects were consistently achieved using cocaine, methylphenidate (MPH), and highly palatable food in marmosets, as well as with morphine and methamphetamine (METH) in macaques. Despite the relatively low number of reports, the available evidence suggests that NHP species represent viable and versatile alternatives for CPP research, offering greater translational validity compared to rodent models due to their closer neurobiological, cognitive, and behavioral similarities to humans.

Cocaine addiction is a chronic disorder with high relapse rates; therefore, understanding the neuronal mechanisms underlying drug-seeking during relapse is a priority to develop targeted pharmacotherapy. The metabotropic glutamate receptor 5 (mGluR5) seems to be involved in the reinstatement induced by cocaine-associated cues. The main objective of the study was to evaluate the efficacy of MPEP, a negative allosteric modulator of mGluR5, in attenuating or potentiating the reinstatement induced by priming doses of cocaine in the CPP paradigm, ultimately to further knowledge regarding the role of the mGluR5 in relapse into cocaine abuse. OF1 mice (48 female and 48 male) were conditioned in the CPP paradigm with cocaine (20 mg/kg) and were exposed to an extinction program. We evaluated the efficacy of MPEP (30 mg/kg) in blocking the successive cocaine-priming reinstatements in the CPP when extinction of the conditioning preference was confirmed. MPEP did not block the reinstatement of priming cocaine-induced CPP, but increased the potential of cocaine for reinstating conditioning preference. The contingent administration of MPEP with cocaine increased the drug-seeking behaviour and the number of reinstatements with priming doses of cocaine. Moreover, MPEP produced cross reinstatement of cocaine-induced CPP. Rather than preventing the reinstatements of conditioned preference induced by priming doses of cocaine, MPEP increased them. These findings may help to understand the role of mGluR5 in the relapse into cocaine abuse.

No abstract available

No abstract available

Altered volumes in the hippocampus and amygdala have been linked to anorexia nervosa (AN). This study aimed to investigate amygdala and hippocampal subfields volume abnormalities in AN patients, and their associations with parental rearing practices and clinical psychological characteristics. This study included twenty-nine drug-naive females with AN from West China Hospital of Sichuan University, China, and fifty-nine age- and gender-matched healthy controls (HCs) recruited through advertisement. All participants underwent T1-weighted imaging. Amygdala and hippocampal subfields volume was calculated using FreeSurfer 7.0. The Core Self-Evaluation Scale (CSES) and Rosenberg Self-Esteem Scale (RSES) were used to assess the psychological characteristics of AN patients. The Egna Minnen av Barndoms Uppfostran (EMBU) was employed to evaluate parental rearing practices. Group differences in brain volumes were analyzed with covariates like age and total intracranial volume (TIV). Partial correlation analysis explored the correlations between brain region volumes and clinical psychological characteristics. AN patients exhibited lower RSES and CSES scores, and more adverse parental rearing style than healthy norms. After adjusting for covariates, AN patients showed decreased gray matter volume (GMV) in the left medial (Me) and cortical (Co) nucleus, as well as in the right hippocampal-amygdala transition area (HATA). GMV in the left Me was correlated with years of education among HCs but not among AN patients. GMV in the right HATA was positively correlated with paternal penalty and severity, as well as maternal overinterference. This study supports structure abnormalities in amygdala and hippocampus in AN patients and suggests that parental rearing practices may be associated with hippocampal abnormalities, potentially contributing to the pathophysiology of AN. Addressing appropriate parental rearing styles may offer a positive impact on AN.

An inadequate response to traumatic experiences due to a loss of plasticity in memory processing could determine the onset of disorders such as post-traumatic stress disorder (PTSD). In this sense, it has been proven that acute stress exposure prior to the encoding of a fear memory alters the plasticity of said memory rendering it unable to undergo a destabilization/reconsolidation process, which is fundamental for memory maintenance and updating. Moreover, it has been shown that inescapable stress induces a hyperexcited state, through loss of GABAergic inhibition in a key structure for fear memory processing such as the basolateral amygdala complex (BLA). In the present study, we sought to elucidate the impact of BLA hyperexcitation, induced by local bicuculline (BIC) infusion, on the hippocampal structural plasticity associated with the destabilization/reconsolidation of contextual fear memories and whether this effect can be prevented or rescued by NMDA receptors modulation. Consistent with previous research, the dendritic spines and behavioural results provide solid evidence that BLA hyperexcitation alters the dorsal hippocampus (DH) involvement in memory reconsolidation in a similar manner to stress exposure. This reinforces the notion that there is a critical interaction between BLA and DH during the processing of this information. In turn, NMDA modulation, through D-cycloserine injection prior to memory reactivation, reverses the effects of BIC infusion. This may be key to identifying new therapeutic targets for the treatment of disorders associated with a maladaptive response to relevant negative emotional events.

Post-traumatic stress disorder (PTSD) is characterized by persistent threat-related memories for which there are limited effective treatment options. The N-methyl-D-aspartate (NMDA) receptor-dependent extracellular signal-regulated kinase (ERK) pathway in the lateral amygdala (LA) is necessary for synaptic plasticity, threat memory consolidation and reconsolidation. Disruption of these memories during the reconsolidation window has been proposed as a therapeutic strategy for PTSD, however, no current therapies using this strategy are available. To disrupt reconsolidation, memories must first be brought into a labile state. We investigated the effect of the NMDA receptor partial agonist D-cycloserine (DCS) and the ketamine-like non-competitive antagonist MK801 on threat memory reconsolidation in mice. Using auditory threat conditioning, DCS, or saline vehicle, was administered one hour before memory reactivation to facilitate labilization of a recalled threat memory, followed by MK801 or a saline vehicle after reactivation. Experimental groups included vehicle, DCS 15 mg/kg, MK801 0.06 mg/kg, and MK801 0.12 mg/kg alone and in combination. The effect of behavioural and drug interventions on phosphor-ERK-expressing neurons in the LA was analysed using neuron counting and topographical mapping in the LA. MK801 alone and in combination with DCS reduced the number of pERK neurons in the LA across all doses. Freezing behaviour was reduced by high-dose MK801 when combined with DCS. These findings suggest that DCS and MK801 together effectively disrupt threat memory reconsolidation in the LA and offer an MDMA-based combined drug and behavioural treatment strategy for PTSD.

Abstract Background Ketamine, an NMDA receptor antagonist, is used in treating psychiatric disorders. While ketamine may induce anxiety-like symptoms acutely, its potential of long-term anxiety alleviation has been discussed (1). Key brain regions implicated in ketamine’s effects include the hippocampus, insula, amygdala, and anterior cingulate cortex (ACC) (2,3), each crucial for emotional processing and fear regulation (4). The hippocampus exerts different functions along its longitudinal axis, with the anterior hippocampus being involved in emotional processing and fear regulation, the posterior hippocampus in memory-retrieval. These functional differences are reflected in different connectivity patterns, with the anterior hippocampus linked to anterior regions, whereas the posterior hippocampus is connecting to posterior areas (5,6). Moreover, our group has recently shown the anterior hippocampus’s role in anxiety-related experiences during a ketamine infusion (7). Aims & Objectives This study aimed to investigate ketamine’s impact on functional connectivity in the aforementioned areas and whether connectivity correlates with the experienced anxiety during infusion. Method Thirty-one healthy volunteers (17 females, 23.2 ± 2.9 years) received in a single-blind, crossover manner either 0.5 mg/kg ketamine or a saline solution four hours before an MRI scan. An anxiety-score was extracted of the 5-Dimensional Altered State of Consciousness questionnaire, completed immediately post-infusion. Functional connectivity was estimated for the anterior hippocampus with the anterior insula (AI), the amygdala with the ACC and the posterior hippocampus with the posterior cingulate cortex (PCC). Differences in functional connectivity between the ketamine and placebo condition were assessed using repeated measures ANOVA. Partial correlations between anxiety scores and functional connectivity were calculated, adjusted for gender. Results A positive correlation between the anxiety-score and the functional connectivity of the anterior hippocampus and the AI (r = 0.449, p = 0.013) as well as of the amygdala and the ACC (r = 0.393, p = 0.032) was observed in the ketamine condition. No such relation emerged between the posterior hippocampus and PCC nor between any region in the placebo condition. Similarly, no significant changes in functional connectivity between the ketamine and the placebo condition were observed. Discussion & Conclusions These correlations suggest the involvement of the anterior hippocampus, AI, amygdala and ACC in the experience of anxiety during a ketamine infusion. These regions are believed to be crucial for fear memory retrieval (8) and reconsolidation (9). Fear memory retrieval is required to destabilize fear memory (10), facilitating fear extinction, which is hypothesized to be enhanced by ketamine (11). Therefore, higher functional connectivity could be associated with enhanced fear processing during the infusion, supporting ketamine’s role in modulating fear processing. While the results are limited as they don’t remain significant after correction for multiple comparison, our results provide initial evidence between anxiety-related experiences and functional connectivity in the anterior hippocampus and AI. Increasing the sample size might enhance the robustness of these findings. Moreover, the MRI scans were conducted four hours post-infusion and might have missed acute changes in functional connectivity. In conclusion, our results support ketamine’s potential for modulating fear memory and anxiety, further studies are required to explore ketamine’s impact on fear extinction.

Maladaptive avoidance behaviour is often observed in patients suffering from anxiety and trauma- and stressor-related disorders. The prefrontal-amygdala-hippocampus network is implicated in learning and memory consolidation. Neuroinflammation in this circuitry alters network dynamics, resulting in maladaptive avoidance behaviour. The two-way active avoidance test is a well-established translational model for assessing avoidance responses to stressful situations. While some animals learn the task and show adaptive avoidance (AA), others show strong fear responses to the test environment and maladaptive avoidance (MA). Here, we investigated if a distinct neuroinflammation pattern in the prefrontal-amygdala-hippocampus network underlies the behavioural difference observed in these animals. Wistar rats were tested 8 times and categorized as AA or MA based on behaviour. Brain recovery followed for the analysis of neuroinflammatory markers in this network. AA and MA presented distinct patterns of neuroinflammation, with MA showing increased astrocyte, EAAT-2, IL-1β, IL-17 and TNF-ɑ in the amygdala. This neuroinflammatory pattern may underlie these animals' fear response and maladaptive avoidance. Further studies are warranted to determine the specific contributions of each inflammatory factor, as well as the possibility of treating maladaptive avoidance behaviour in patients with psychiatric disorders with anti-inflammatory drugs targeting the amygdala.

BACKGROUND Cannabis is the most frequently used illicit drug worldwide. Although multiple structural MRI studies of individuals with cannabis use (CB) have been undertaken, the reports of the volume alterations in the amygdala, hippocampus, and pallidum are not consistent. This study aims to detect subregion-level morphological alterations, analyze the correlation areas with cannabis usage characteristics, and gain new insights into the neuro mechanisms of CB. METHODS By leveraging the novel surface-based subcortical morphometry method, 20 CB and 22 age- and sex-matched healthy controls (HC) were included to explore their volumetric and morphological differences in the three subcortical structures. Afterward, the correlation analysis between surface morphological eigenvalues and cannabis usage characteristics was performed. RESULTS Compared with volumetric measures, the surface-based subcortical morphometry method detected more significant global morphological deformations in the left amygdala, right hippocampus, and right pallidum (overall-p < 0.05, corrected). More obvious morphological alterations (atrophy or expansion) were observed in specific subregions (vertex-based p-value<0.05, uncorrected) of the three subcortical structures. Both positive and negative subregional correlation areas were reported by the correlation analysis. CONCLUSIONS The current study illuminated new pathophysiologic mechanisms in the amygdala, hippocampus, and pallidum at the subregion level, which may inform the subsequent smaller-scale CB research.

Suicide is one of the leading causes of death globally for all ages, and as such presents a very serious problem for clinicians worldwide. However, the underlying neurobiological pathology remains to a large extent unknown. In order to address this gap, we have carried out a genome-wide investigation of the gene expression in the amygdala, hippocampus, prefrontal cortex and thalamus in post-mortem brain samples obtained from 20 suicide completers and 7 control subjects. By KEGG enrichment analysis indicated we identified novel clusters of downregulated pathways involved in antigen neutralization and autoimmune thyroid disease (amygdala, thalamus), decreased axonal plasticity in the hippocampus. Two upregulated pathways were involved in neuronal death in the hippocampus and olfactory transduction in the thalamus and the prefrontal cortex. Autoimmune thyroid disease pathway was downregulated only in females. Metabolic pathways involved in Notch signaling amino acid metabolism and unsaturated lipid synthesis were thalamus-specific. Suicide-associated changes in the expression of several genes and pseudogenes that point to various functional mechanisms possibly implicated in the pathology of suicide. Two genes (SNORA13 and RNU4-2) involved in RNA processing were common to all brain regions analyzed. Most of the identified gene expression changes were related to region-specific dysregulated manifestation of genetic and epigenetic mechanisms underlying neurodevelopmental disorders (SNORD114-10, SUSd1), motivation, addiction and motor disorders (CHRNA6), long-term depression (RAB3B), stress response, major depression and schizophrenia (GFAP), signal transduction at the neurovascular unit (NEXN) and inhibitory neurotransmission in spatial learning, neural plasticity (CALB2; CLIC6, ENPP1). Some of the differentially expressed genes were brain specific non-coding RNAs involved in the regulation of translation (SNORA13). One, (PARM1) is a potential oncogene and prognostic biomarker for colorectal cancer with no known function in the brain. Disturbed gene expression involved in antigen neutralization, autoimmunity, neural plasticity, stress response, signal transduction at the neurovascular unit, dysregulated nuclear RNA processing and translation and epigenetic imprinting signatures is associated with suicide and point to regulatory non-coding RNAs as potential targets of new drugs development.

Anxiety and depression exhibit high comorbidity and share the alteration of the amygdala–hippocampal–prefrontal network, playing different roles in the ventral and dorsal hippocampi. Deep brain stimulation of the infralimbic cortex in rodents or the human equivalent—the subgenual cingulate cortex—constitutes a fast antidepressant treatment. The aim of this work was: (1) to describe the oscillatory profile in a rodent model of anxiety, and (2) to deepen the therapeutic basis of infralimbic deep brain stimulation in mood disorders. First, the anxiogenic drug FG-7142 was administered to anaesthetized rats to characterize neural oscillations within the amygdala and the dorsoventral axis of the hippocampus. Next, deep brain stimulation was applied. FG-7142 administration drastically reduced the slow waves, increasing delta, low theta, and beta oscillations in the network. Moreover, FG-7142 altered communication in these bands in selective subnetworks. Deep brain stimulation of the infralimbic cortex reversed most of these FG-7142 effects. Cross-frequency coupling was also inversely modified by FG-7142 and by deep brain stimulation. Our study demonstrates that the hyperactivated amygdala–hippocampal network associated with the anxiogenic drug exhibits an oscillatory fingerprint. The study contributes to comprehending the neurobiological basis of anxiety and the effects of infralimbic deep brain stimulation.

Reconsolidation is a process in which re-exposure to a reminder causes a previously acquired memory to undergo a process of destabilisation followed by subsequent restabilisation. Different molecular mechanisms have been postulated for destabilisation in the amygdala and hippocampus, including CB1 receptor activation, protein degradation and AMPA receptor exchange; however, most of the amygdala studies have used pre-reexposure interventions, while those in the hippocampus have usually performed them after reexposure. To test whether the temporal window for destabilisation is similar across both structures, we trained Lister Hooded rats in a contextual fear conditioning task, and 1 day later performed memory reexposure followed by injection of either the NMDA antagonist MK-801 (0.1 mg/kg) or saline in order to block reconsolidation. In parallel, we also performed local injections of either the CB1 antagonist SR141716A or its vehicle in the hippocampus or in the amygdala, either immediately before or immediately after reactivation. Infusion of SR141716A in the hippocampus prevented the reconsolidation-blocking effect of MK-801 when performed after reexposure, but not before it. In the amygdala, meanwhile, pre-reexposure infusions of SR141716A impaired reconsolidation blockade by MK-801, although the time-dependency of this effect was not as clear as in the hippocampus. Our results suggest the temporal windows for CB1-receptor-mediated memory destabilisation during reconsolidation vary between brain structures. Whether this reflects different time windows for engagement of these structures or different roles played by CB1 receptors in destabilisation across structures remains an open question for future studies.

Post Traumatic Stress Disorder (PTSD) patients often show excessive fear generalization to harmless cues. Animal model studies illustrate that, hippocampus and medial prefrontal cortex (mPFC) play important roles in the process of discrimination and generalization of fear memories: as the hippocampus maintain the accuracy of memory through pattern separation and neurogenic mechanisms, mPFC regulates the separation of fear and safe stimuli via the neuroplasticity mechanism mediated by excitatory NMDA receptors. mPFC and hippocampus coordinate emotional valence through the hippocampus-amygdala circuit, achieving the remote updating of memories. If the reconsolidation process of the hippocampus of mPFCs regulation function are unbalanced, the fear memory would remain coarse cortical representation, which increases memory generalization. Understanding these mechanisms would be useful to help conduct the targeted intervention of PTSD, such as promoting the forgetting of the traumatic memories through enhancing the neurogenesis in the hippocampus, and improving the recognition of fear cues through regulating mPFC networks, which could help undermine the symptom of excessive generalization.

Extinction is the learned inhibition of retrieval. It is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear-related pathologies such as post-traumatic stress disorder. The serotonin (5-HT) system is positioned to modulate the extinction circuitry via ascending 5-HT projections that innervate certain brain structures including the hippocampus and the basolateral amygdala (BLA). The most recently described serotoninergic receptors 5-HT5A, 5-HT6, 5-HT7 affect different memory processes and so are putative therapeutic targets for disorders related to cognition; however, their role in the extinction of contextual fear conditioning (CFC) has not been studied yet. Here we investigate the role of these receptors in the CA1 region of the hippocampus and the BLA in the extinction of CFC. For this, male rats were implanted with cannulae in the CA1 or in the BLA region through which they received immediately or 3 h after extinction training of CFC infusions of SB699551 (10 µg/side), 5-HT5A antagonist; WAY-208466 (0.04 µg/side), 5-HT6 agonist; SB-271046A (10 µg/side), 5-HT6 antagonist; AS-19 (5 µg/side), 5-HT7 agonist; SB-269970 (5 µg/side), 5-HT7 antagonist. After 24 h, animals were submitted to a 3 min extinction test. Results show that the infusion immediately after extinction training of 5-HT5A, 5-HT6 and 5-HT7 antagonists, and 3 h after extinction training of 5-HT5A and 5-HT7 antagonists in the BLA region, but not in CA1, facilitates the extinction of CFC memory.

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An isoform of peroxisome proliferator-activated receptors (PPARs), PPARγ, is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. Neuroanatomical data indicate PPARγ localization in brain areas involved in drug addiction. Preclinical and clinical data have shown that pioglitazone reduces alcohol and opioid self-administration, relapse to drug seeking, and plays a role in emotional responses. An isoform of peroxisome proliferator-activated receptors (PPARs), PPARγ, is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. Neuroanatomical data indicate PPARγ localization in brain areas involved in drug addiction. Preclinical and clinical data have shown that pioglitazone reduces alcohol and opioid self-administration, relapse to drug seeking, and plays a role in emotional responses. Here, we investigated the behavioral effect of PPARγ manipulation on nicotine withdrawal in male Wistar rats and in male mice with neuron-specific PPARγ deletion (PPARγ(−/−)) and their littermate wild-type (PPARγ(+/+)) controls. Real-time quantitative RT-PCR and RNAscope in situ hybridization assays were used for assessing the levels of expression and cell-type localization of PPARγ during nicotine withdrawal. Brain site-specific microinjections of the PPARγ agonist pioglitazone were performed to explore the role of this system on nicotine withdrawal at a neurocircuitry level. Results showed that activation of PPARγ by pioglitazone abolished the expression of somatic and affective nicotine withdrawal signs in rats and in (PPARγ(+/+)) mice. This effect was blocked by the PPARγ antagonist GW9662. During early withdrawal and protracted abstinence, the expression of PPARγ increased in GABAergic and glutamatergic cells of the amygdala and hippocampus, respectively. Hippocampal microinjections of pioglitazone reduced the expression of the physical signs of withdrawal, whereas excessive anxiety associated with protracted abstinence was prevented by pioglitazone microinjection into the amygdala. Our results demonstrate the implication of the neuronal PPARγ in nicotine withdrawal and indicates that activation of PPARγ may offer an interesting strategy for smoking cessation. SIGNIFICANCE STATEMENT Smoking cessation leads the occurrence of physical and affective withdrawal symptoms representing a major burden to quit tobacco use. Here, we show that activation of PPARγ prevents the expression of both somatic and affective signs of nicotine withdrawal. At molecular levels results show that PPARγ expression increases in GABAergic cells in the hippocampus and in GABA- and glutamate-positive cells in the basolateral amygdala. Hippocampal microinjections of pioglitazone reduce the insurgence of the physical withdrawal signs, whereas anxiety linked to protracted abstinence is attenuated by pioglitazone injected into the amygdala. Our results demonstrate the implication of neuronal PPARγ in nicotine withdrawal and suggest that PPARγ agonism may represent a promising treatment to aid smoking cessation.

HighlightsReactivation of opiate withdrawal memories suppresses operant behavior for food.Context effect on behavioral responding is invigorated by the cue.catFISH for Arc expression differentiates context and cue influences on behavioral.Specific reactivity in NAC‐BLA‐HPC network discriminates these differential responses. Abstract Opiate withdrawal induces an early aversive state which can be associated to contexts and/or cues, and re‐exposure to either these contexts or cues may participate in craving and relapse. Nucleus accumbens (NAC), hippocampus (HPC) and basolateral amygdala (BLA) are crucial substrates for acute opiate withdrawal, and for withdrawal memory retrieval. Also HPC and BLA interacting with the NAC are suggested to respectively mediate the processing of context and cue representations of drug‐related memories. Here we used a paradigm of conditioned suppression of operant food seeking, allowing to differentiate context and cue related responses, to study the influence of withdrawal memories on operant behavior and the underlying neural substrates. catFISH for Arc mRNA expression was used to discriminate cellular responses during context and cue (flashing light) periods in this paradigm. We show that reactivation of the memory of the negative affective state of withdrawal suppresses active lever pressing for food, and this conditioned suppression is generalized to the context. Interestingly the behavioral responses during the context and cue light periods are associated with differential Arc mRNA activations within the NAC, BLA, and HPC. Indeed both periods led to NAC shell activation whereas the NAC core was responsive only following the cue light period. Moreover, BLA and HPC were more responsive during cue‐light and context period respectively. These data further support the already reported differential role of these brain structures on cue vs context‐induced reinstatement of operant behaviors, and highlight the existence of common mechanisms for the processing of positive and aversive emotional memories.

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BACKGROUND Preclinical rodent studies have demonstrated reduced cocaine taking after administration of glucagon-like peptide 1 (GLP-1) analogues. We investigated effects of a GLP-1 analogue (exenatide) on behavioral and subjective effects of cocaine in individuals with cocaine use disorder (CUD). METHODS Non-treatment-seeking CUD subjects underwent two human laboratory cocaine self-administration test sessions following an acute 3 -h pre-treatment with exenatide (5 mcg; subcutaneously) or placebo. Primary outcomes consisted of infusions of cocaine and visual analog scale self-ratings of euphoria and wanting cocaine. Secondary outcomes consisted of pertinent hormone levels (GLP-1, insulin, and amylin). RESULTS Thirteen individuals completed the study. Acute pretreatment with exenatide versus placebo did not change cocaine infusions (8.5 ± 1.2 vs. 9.1 ± 1.2; p = 0.39), self-reported euphoria (4.4 ± 0.8 vs. 4.1 ± 0.8; p = 0.21), or wanting of cocaine (5.6 ± 0.9 vs. 5.4 ± 0.9; p = 0.46). Exenatide vs. placebo reduced levels of GLP-1 (p = 0.03) and insulin (p = 0.02). Self-administered cocaine also reduced levels of GLP-1 (p < 0.0001), insulin (p < 0.0001), and amylin (p < 0.0001). CONCLUSIONS We did not find evidence that low dose exenatide alters cocaine self-administration or the subjective effects of cocaine in people with CUD. Limitations such as single acute rather than chronic pre-treatment, as well as evaluation of only one dose, preclude drawing firm conclusions about the efficacy of exenatide. Exenatide and cocaine independently reduced levels of GLP-1 and insulin, while cocaine also reduced levels of amylin.

Abstract Cocaine addiction is a devastating public health epidemic that continues to grow. Studies focused on identifying biological factors influencing cocaine craving and relapse vulnerability are necessary to promote abstinence in recovering drug users. Sex and ovarian hormones are known to influence cocaine addiction liability and relapse vulnerability in both humans and rodents. Previous studies have investigated sex differences in the time-dependent intensification or “incubation” of cue-induced cocaine craving that occurs during withdrawal from extended-access cocaine self-administration and have identified changes across the rat reproductive cycle (estrous cycle). Female rats in the estrus stage of the cycle (Estrus Females), the phase during which ovulation occurs, show an increase in the magnitude of incubated cue-induced cocaine craving compared with females in all other phases of the estrous cycle (Non-Estrus Females). Here we extend these findings by assessing incubated craving across the estrous cycle during earlier withdrawal periods (withdrawal day 1 and 15) and later withdrawal periods (withdrawal day 48). We found that this increase in the magnitude of incubated craving during estrus (Estrus Females) is present on withdrawal day 15, but not on withdrawal day 1, and further increases by withdrawal day 48. No difference in the magnitude of incubated craving was observed between Males and Non-Estrus Females. Our data indicate that the effects of hormonal fluctuations on cue-induced cocaine craving intensify during the first month and a half of withdrawal, showing an interaction among abstinence length, estrous cycle fluctuations, and cocaine craving.

With the rise of e-cigarette use, teen nicotine exposure is becoming more widespread. Findings from clinical and preclinical studies show that the adolescent brain is particularly sensitive to nicotine. Animal studies have demonstrated that adolescent nicotine exposure increases reinforcement for cocaine and other drugs. However, the mechanisms that underlie these behaviors are poorly understood. Here, we report reactive microglia are critical regulators of nicotine-induced increases in adolescent cocaine self-administration. Nicotine has dichotomous, age-dependent effects on microglial morphology and immune transcript profiles. A multistep signaling mechanism involving D2 receptors and CX3CL1 mediates nicotine-induced increases in cocaine self-administration and microglial activation. Moreover, nicotine depletes presynaptic markers in a manner that is microglia-, D2- and CX3CL1-dependent. Taken together, we demonstrate that adolescent microglia are uniquely susceptible to perturbations by nicotine, necessary for nicotine-induced increases in cocaine-seeking, and that D2 receptors and CX3CL1 play a mechanistic role in these phenomena. Adolescents are particularly sensitive to nicotine. Here the authors show that in mice, microglial activation contributes to the enhanced sensitivity to cocaine caused by nicotine exposure in young mice.

BACKGROUND Global changes in gene expression underlying circuit and behavioral dysregulation associated with cocaine addiction remain incompletely understood. Here, we show how a history of cocaine self-administration (SA) reprograms transcriptome-wide responses throughout the brain's reward circuitry at baseline and in response to context and/or cocaine re-exposure after prolonged withdrawal (WD). METHODS We assigned male mice to one of six groups: saline/cocaine SA + 24-hour WD or saline/cocaine SA + 30-day WD + an acute saline/cocaine challenge within the previous drug-paired context. RNA sequencing was conducted on six interconnected brain reward regions. Using pattern analysis of gene expression and factor analysis of behavior, we identified genes that are strongly associated with addiction-related behaviors and uniquely altered by a history of cocaine SA. We then identified potential upstream regulators of these genes. RESULTS We focused on three patterns of gene expression that reflect responses to 1) acute cocaine, 2) context re-exposure, and 3) drug + context re-exposure. These patterns revealed region-specific regulation of gene expression. Further analysis revealed that each of these gene expression patterns correlated with an addiction index-a composite score of several addiction-like behaviors during cocaine SA-in a region-specific manner. Cyclic adenosine monophosphate response element binding protein and nuclear receptor families were identified as key upstream regulators of genes associated with such behaviors. CONCLUSIONS This comprehensive picture of transcriptome-wide regulation in the brain's reward circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.

Substance use is strongly associated with impaired decision making, with cocaine use particularly linked to elevated risky and impulsive choice. It is not clear, however, whether such maladaptive decision making is a consequence of cocaine use or instead precedes and predisposes individuals to cocaine use. The current study was designed to specifically address the latter possibility with respect to risky choice in both male and female rats. Rats were first trained in a "Risky Decision-making Task" (RDT), in which they made discrete choices between a small, "safe" food reward and a large, "risky" food reward accompanied by increasing probabilities of mild footshock punishment. After reaching stable performance, rats underwent jugular catheter surgery followed by either short-access cocaine self-administration sessions (2 h, 0.5 mg/kg/infusion) for 5 days or long-access cocaine self-administration sessions (6 h, 0.5 mg/kg/infusion) for 14 days. Under short-access conditions, there was no relationship between risk preference and changes in cocaine intake over time, but greater risk aversion in females predicted greater overall cocaine intake. Under long-access conditions, heightened risk taking predicted greater escalation of cocaine intake over the course of self-administration, supporting the notion that pre-existing risk-taking behavior predicts cocaine intake. Collectively, results from these experiments have implications for understanding and identifying pre-existing vulnerabilities to substance use, which may lead to strategies to prevent development of substance use disorders.

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A widely accepted rodent model to study cocaine addiction involves allowing animals continuous access to drug during long self-administration sessions (‘Long-access’ or LgA). This produces continuously high brain concentrations of drug during each session. This might not model the pharmacokinetics of cocaine use in experienced human users, which are thought to involve intermittently spiking brain cocaine concentrations within and between bouts of use. Intermittent-access (IntA) cocaine self-administration models this spiking pattern in rats. IntA is also particularly effective in increasing incentive motivation for drug. Most IntA studies have been conducted in male rats. Both humans and non-human animals can show sex differences in all phases of the addiction process. We compared cocaine use in female and male rats that self-administered the drug (0.25 mg/kg/injection, i.v.) during 10 daily, 6-h LgA or IntA sessions. Cocaine intake was greatest under LgA, and female LgA rats escalated their intake. However, only IntA rats (both sexes) developed locomotor sensitization to self-administered cocaine and sensitization was greatest in the females. Five and 25 days after the last self-administration session, we quantified incentive motivation for cocaine by measuring breakpoints for the drug (0.083-0.75 mg/kg/injection) under progressive ratio. Breakpoints were similar in IntA and LgA rats. There were no sex differences in breakpoints under LgA. However, under IntA, females reached higher breakpoints for cocaine than males. Thus, LgA might be best suited to study sex differences in cocaine intake, while IntA might be best suited to study sex differences in incentive motivational processes in cocaine addiction.

Background Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex may serve as a potential treatment for cocaine use disorder (CUD), which remains a public health problem that is refractory to treatment. The goal of this pilot study was to investigate the effect of rTMS on cocaine self-administration in the laboratory. In the self-administration sessions, CUD participants chose between cocaine and an alternative reinforcer (money) in order to directly measure cocaine-seeking behavior. The rTMS was delivered with the H7 coil, which provides stimulation to the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). These brain regions were targeted based on previous imaging studies demonstrating alterations in their activation and connectivity in CUD. Methods Volunteers with CUD were admitted to an inpatient unit for the entire study and assigned to one of three rTMS groups: high frequency (10 Hz), low frequency (1 Hz), and sham. Six participants were included in each group and the rTMS was delivered on weekdays for 3 weeks. The cocaine self-administration sessions were performed at three time points: at baseline (pre-TMS, session 1), after 4 days of rTMS (session 2), and after 13 days of rTMS (session 3). During each self-administration session, the outcome measure was the number of choices for cocaine. Results The results showed a significant group by time effect (p = 0.02), where the choices for cocaine decreased between sessions 2 and 3 in the high frequency group. There was no effect of rTMS on cocaine self-administration in the low frequency or sham groups. Conclusion Taken in the context of the existing literature, these results contribute to the data showing that high frequency rTMS to the prefrontal cortex may serve as a potential treatment for CUD.

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In rats, continuous cocaine access during long self‐administration sessions (6 versus 1–2 hours) promotes the development of behavioral symptoms of addiction. This has led to the assumption that taking large amounts of drug during extended daily bouts is necessary to develop an addiction phenotype. Recent work shows that within‐session intermittent access (IntA) to cocaine produces much less drug intake than continuous‐access procedures (i.e. long‐access sessions) but evokes addiction symptoms more effectively. IntA‐sessions are also long, typically lasting 6 hours. It is not known whether IntA‐sessions must be extended to promote addiction‐relevant changes in drug use over time. Here, we determined the influence of IntA‐session length on patterns of cocaine use relevant to addiction. Two groups of male Wistar rats self‐administered cocaine (0.25 mg/kg/injection, injected over 5 seconds) during 18 daily IntA‐sessions. One group had long 6‐hour sessions (Long‐IntA), the other group had shorter, 2‐hour sessions (Short‐IntA). Only Long‐IntA rats escalated their cocaine intake over sessions, but both groups developed a burst‐like pattern of drug use over time and similar levels of psychomotor sensitization. The two groups also showed robust and similar levels of both responding for cocaine under a progressive ratio schedule of reinforcement and cocaine‐induced reinstatement of extinguished drug‐seeking behavior. In summary, long IntA‐sessions lead to greater cocaine intake than shorter IntA‐sessions, but the two conditions are equally effective in evoking the patterns of drug‐taking and drug‐seeking that define addiction. This suggests that chronic intermittent cocaine use, even during short daily bouts, is sufficient to promote addiction symptoms.

Early-life adversity increases the risk for emotional disorders such as depression and schizophrenia. Anhedonia, thought to be a core feature of these disorders, is provoked by our naturalistic rodent model of childhood adversity (i.e., rearing pups for one week in cages with limited bedding and nesting, LBN). Drug use and addiction are highly comorbid with psychiatric disorders featuring anhedonia, yet effects of LBN on drug-seeking behavior and the reward and stress-related circuits that underlie it remain unknown. Here we examined the effects of LBN on cocaine intake and seeking, using a battery of behavioral tests measuring distinct aspects of cocaine reward, and for comparison, chocolate intake. We also examined activation of neurons within the pleasure/reward and stress circuits following cocaine in LBN and control rats. Early-life adversity reduced spontaneous intake of palatable chocolate, extending prior reports of sucrose and social-play anhedonia. In a within-session cocaine behavioral economic test, LBN rats self-administered lower dosages of cocaine under low-effort conditions, consistent with a reduced hedonic set-point for cocaine, and potentially anhedonia. In contrast, cocaine demand elasticity was not consistently affected, indicating no major changes in motivation to maintain preferred cocaine blood levels. These changes were selective, as LBN did not cause an overt anxiety-like phenotype, nor did it affect sensitivity to self-administered cocaine dose, responding for cocaine under extinction conditions, cocaine- or cue-induced reinstatement of cocaine seeking, or locomotor response to acute cocaine. However, high Fos expression was seen after cocaine in both reward- and stress-related brain regions of LBN rats, including nucleus accumbens core, central amygdala, and lateral habenula. In contrast, hypothalamic orexin neuron activation after cocaine was significantly attenuated in LBN rats. Together, these findings demonstrate enduring effects of early-life adversity on both reward- and fear/anxiety-related neural circuits, as well as anhedonia-like reductions in consumption of natural and drug rewards.

Antagonistic allosteric A2AR-D2R receptor-receptor interactions in heteroreceptor complexes counteract cocaine self-administration and cocaine seeking in rats as seen in biochemical and behavioral experiments. It was shown that the human A2AR transmembrane five (TM5) was part of the interface of the human A2AR-D2R receptor heteromer. In the current paper, the rat A2AR synthetic TM5 (synthTM5) peptide disrupts the A2AR-D2R heteroreceptor complex in HEK293 cells as shown by the bioluminescence resonance energy transfer method. Rat A2AR synthTM5 peptide, microinjected into the nucleus accumbens, produced a complete counteraction of the inhibitory effects of the A2AR agonist CGS21680 on cocaine self-administration. It was linked to a disappearance of the accumbal A2AR-D2R heteroreceptor complexes and the A2AR agonist induced inhibition of D2R recognition using proximity ligation assay and biochemical binding techniques. However, possible effects of the A2AR synthTM5 peptide on accumbal A2AR-D3R and A2AR-D4R heteroreceptor complexes remain to be excluded. Evidence is provided that accumbal A2AR-D2R-like heteroreceptor complexes with their antagonistic receptor-receptor interactions can be major targets for treatment of cocaine use disorder.

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Central ghrelin signaling seems to play important role in addiction as well as memory processing. Antagonism of the growth hormone secretagogue receptor (GHS-R1A) has been recently proposed as a promising tool for the unsatisfactory drug addiction therapy. However, molecular aspects of GHS-R1A involvement in specific brain regions remain unclear. The present study demonstrated for the first time that acute as well as subchronic (4 days) administration of the experimental GHS-R1A antagonist JMV2959 in usual intraperitoneal doses including 3 mg/kg, had no influence on memory functions tested in the Morris Water Maze in rats as well as no significant effects on the molecular markers linked with memory processing in selected brain areas in rats, specifically on the β-actin, c-Fos, two forms of the calcium/calmodulin-dependent protein kinase II (CaMKII, p-CaMKII) and the cAMP-response element binding protein (CREB, p-CREB), within the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum, and hippocampus (HIPP). Furthermore, following the methamphetamine intravenous self-administration in rats, the 3 mg/kg JMV2959 pretreatment significantly reduced or prevented the methamphetamine-induced significant decrease of hippocampal β-actin and c-Fos as well as it prevented the significant decrease of CREB in the NAC and mPFC. These results imply, that the GHS-R1A antagonist/JMV2959 might reduce/prevent some of the memory-linked molecular changes elicited by methamphetamine addiction within brain structures associated with memory (HIPP), reward (NAc), and motivation (mPFC), which may contribute to the previously observed significant JMV2959-induced reduction of the methamphetamine self-administration and drug-seeking behavior in the same animals. Further research is necessary to corroborate these results.

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The purinergic P2X7 receptors (P2X7R) are activated by adenosine triphosphate (ATP) in several brain regions, particularly those involved with emotional control and the regulation of fear-related memories. Here, we investigate the role of P2X7R in fear learning memory, specifically in the acquisition and consolidation phases of the cued fear conditioning paradigm. C57Bl/6 wildtype (WT) male mice that received a single i.p. injection of the selective P2X7R antagonist A438079 prior the conditioning session showed generalization of cued fear memory and impaired fear extinction recall in the test session, while those treated prior the extinction session exhibited a similar behavior profile accompanied by resistance in the extinction learning. However, no effects were observed when this drug was administered immediately after the conditioning, extinction, or before the test session. Our results with P2X7R knockout (P2X7 KO) mice showed a behavioral profile that mirrored the collective effects observed across all pharmacological treatment conditions. This suggests that the P2X7R KO model effectively replicates the behavioral changes induced by the pharmacological interventions, demonstrating that we have successfully isolated the role of P2X7R in the fear and extinction phases of memory. These findings highlight the role of P2X7R in the acquisition and recall of extinction memory and supports P2X7R as a promising candidate for controlling abnormal fear processing, with potential applications for stress exposure-related disorders such as post-traumatic stress disorder (PTSD).

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Aberrant patterns of brain functional connectivity in the default mode network (DMN) have been observed across different classes of substance use disorder (SUD) and are associated with craving and relapse. In addicted individuals resting functional connectivity (RSFC) of the anterior DMN, which participates in attribution of personal value and emotional regulation, tends to be decreased, whereas RSFC of the posterior DMN, which directs attention to the internal world, tends to be increased. Aberrant RSFC within the DMN is believed to contribute to impaired self-awareness, negative emotions and to ruminations in addiction. Additionally, the disrupted connectivity between DMN and cortical regions involved with executive function, memory and emotion could be critical to drug-taking regardless of negative consequences and to stress-triggered relapse. At the system level, the dynamics of DMN interactions with the executive control and the salience networks are also disturbed in addiction. The DMN is prominently engaged during the withdrawal and preoccupation phases of the addiction cycle at the expense of the executive control network and with an enhanced participation of the salience network. In contrast, DMN prominence appears to be transitorily decreased during the intoxication phases. There is also growing evidence that disruption of the DMN in addiction reflects in part changes in dopaminergic, glutamatergic, and GABAergic signaling associated with acute and chronic drug use. Findings are starting to reveal DMN RSFC as a potential biomarker for predicting clinical outcomes in SUD and identify the DMN as a promising target for the treatment of addiction.

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Drug abuse changes neurophysiological functions at multiple cellular and molecular levels in the addicted brain. Well-supported scientific evidence suggests that drugs negatively affect memory formation, decision-making and inhibition, and emotional and cognitive behaviors. The mesocorticolimbic brain regions are involved in reward-related learning and habitual drug-seeking/taking behaviors to develop physiological and psychological dependence on the drugs. This review highlights the importance of specific drug-induced chemical imbalances resulting in memory impairment through various neurotransmitter receptor-mediated signaling pathways. The mesocorticolimbic modifications in the expression levels of brain-derived neurotrophic factor (BDNF) and the cAMP-response element binding protein (CREB) impair reward-related memory formation following drug abuse. The contributions of protein kinases and microRNAs (miRNAs), along with the transcriptional and epigenetic regulation have also been considered in memory impairment underlying drug addiction. Overall, we integrate the research on various types of drug-induced memory impairment in distinguished brain regions and provide a comprehensive review with clinical implications addressing the upcoming studies.

Emotions, in general, have no scientific definition. Emotions can be denoted as the mental state because of the neurophysiological changes. Emotions are related to mood, personality, temperament, and consciousness. People exhibit different emotions in different situations causing changes in cognitive functions. One of the major cognitive functions is the ability to learn, to store the acquired information in the parts of the brain such as the hippocampus, amygdala, cortex, and cerebellum. Learning and memory are affected by different types of emotions. Emotional responses such as fear, depression, and stress have impaired effects on cognitive functions such as learning and memory, whereas optimistic and happy emotions have positive effects on long-term memory. Certain disorders have greater effects on the regions of the brain which are also associated with synaptic plasticity and Learning and Memory(LM). Neuroimaging techniques are involved in studying the changing regions of the brain due to varied emotions and treatment strategies based on the changes observed. There are many drugs, and in advancements, nanotechnology is also utilized in the treatment of such psychiatric disorders. To improve mental health and physical health, emotional balance is most important, and effective care should be provided for people with less emotional quotient and different types of disorders to inhibit cognitive dysfunctions. In this review, emotions and their varied effects on a cognitive function named learning and memory, disorders associated with the defects of learning due to emotional instability, the areas of the brain that are in control of emotions, diagnosis, and treatment strategies for psychiatric disorders dependent on emotions are discussed.

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The state-dependent memory defines as a state that the retrieval of recently obtained information may be potential if the subject exists in a similar physiological situation as for the period of the encoding stage. Studies revealed that exogenous and endogenous compounds could induce state-dependent memory. The state-dependent memory made it probable to differentiate the effects of drugs per se on learning from the effects due to alterations in drug state during the task. Studies proposed the role of regions beyond the limbic formation and illustrated that state-dependent memory produced by various neurotransmitter systems and pharmacological compounds. Our review of the literature revealed that: (a) re-administration of drugs on the same state induce state-dependent memory; (b) many neurotransmitters induce endogenous state-dependent memory; (c) there are cross state-dependent learning and memory between some drugs; (d) some sites of the brain including the CA1 areas of the hippocampus, central nucleus of the amygdala (CeA), septum, ventral tegmental area (VTA), and nucleus accumbens (NAC) are involved in state-dependent memory. See also Figure 1(Fig. 1).

Fear is characterized by distinct behavioral and physiological responses that are essential for the survival of the human species. Fear conditioning (FC) serves as a valuable model for studying the acquisition, extinction, and expression of fear. The serotonin (5-hydroxytryptamine, 5-HT) system is known to play a significant role in emotional and motivational aspects of human behavior, including fear learning and expression. Accumulating evidence from both animal and human studies suggests that brain regions involved in FC, such as the amygdala, hippocampus, and prefrontal cortex, possess a high density of 5-HT receptors, implicating the crucial involvement of serotonin in aversive learning. Additionally, studies exploring serotonin gene polymorphisms have indicated their potential influence on FC. Therefore, the objective of this work was to review the existing evidence linking 5-HT with fear learning and memory in humans. Through a comprehensive screening of the PubMed and Web of Science databases, 29 relevant studies were included in the final review. These studies investigated the relationship between serotonin and fear learning using drug manipulations or by studying 5-HT-related gene polymorphisms. The results suggest that elevated levels of 5-HT enhance aversive learning, indicating that the modulation of serotonin 5-HT2A receptors regulates the expression of fear responses in humans. Understanding the role of this neurochemical messenger in associative aversive learning can provide insights into psychiatric disorders such as anxiety and post-traumatic stress disorder (PTSD), among others.

Population-based studies have shown that the intake of Angiotensin-II receptor blockers (ARBs), commonly used to treat high blood pressure, is associated with reduced post-traumatic stress disorder (PTSD) symptoms. However, the underlying neural mechanisms remain unclear. While PTSD development is characterized by maladaptive processing within brain networks associated with fear processing and memory formation during trauma exposure, there is increasing evidence that such aberrations manifest in altered resting state functional connectivity (rsFC) of brain regions in these networks. In this double-blind placebo-controlled study in 45 healthy volunteers with high trait-anxiety, we investigated whether the ARB losartan would affect rsFC in prominent seeds of the fear and memory network, counteracting effects seen in PTSD. Seed selection was informed by established rsFC aberrations seen in PTSD and consisted of the hippocampus and the parahippocampal gyrus (memory network), as well the amygdala and insula (fear network). Our results showed that a single dose of the ARB losartan decreased rsFC in the memory network from modulatory structures in the frontal cortex: losartan decreased rsFC (i) between the hippocampus and the inferior frontal gyrus involved in threat processing and memory intrusion development, and (ii) between the parahippocampal gyrus and the dorsolateral prefrontal cortex involved in top-down control. There were no drug effects on the fear network seeds. These findings may imply that ARB preserves adaptive memory function during trauma.