Reconsolidation Blockade Research Articles

Targeting fear memories: Examining pharmacological disruption in a generalized fear framework

Labilization-reconsolidation, which relies on retrieval, has been considered an opportunity to attenuate the negative aspects of traumatic memories. A therapeutic strategy based on reconsolidation blockade is deemed more effective than current therapies relying on memory extinction. Nevertheless, extremely stressful memories frequently prove resistant to this process. Here, after inducing robust fear memory in mice through strong fear conditioning, we examined the possibility of rendering it susceptible to pharmacological modulation based on the degree of generalized fear (GF). To achieve this, we established an ordered gradient of GF, determined by the perceptual similarity between the associated context (CA) and non-associated contexts (CB, CC, CD, and CE) to the aversive event. We observed that as the exposure context became less similar to CA, the defensive pattern shifted from passive to active behaviors in both male and female mice. Subsequently, in conditioned animals, we administered propranolol after exposure to the different contexts (CA, CB, CC, CD or CE). In males, propranolol treatment resulted in reduced freezing time and enhanced risk assessment behaviors when administered following exposure to CA or CB, but not after CC, CD, or CE, compared to the control group. In females, a similar change in behavioral pattern was observed with propranolol administered after exposure to CC, but not after the other contexts. These results highlight the possibility of indirectly manipulating a robust contextual fear memory by controlling the level of generalization during recall. Additionally, it was demonstrated that the effect of propranolol on reconsolidation would not lead to a reduction in fear memory per se, but rather to its reorganization resulting in greater behavioral flexibility (from passive to active behaviors). Finally, from a clinical viewpoint, this would be of considerable relevance since following this strategy could make the treatment of psychiatric disorders associated with traumatic memory formation more effective and less stressful.

Dual-step pharmacological intervention for traumatic-like memories: implications from D-cycloserine and cannabidiol or clonidine in male and female rats.

Therapeutic approaches to mitigating traumatic memories have often faced resistance. Exploring safe reconsolidation blockers, drugs capable of reducing the emotional valence of the memory upon brief retrieval and reactivation, emerges as a promising pharmacological strategy. Towards this objective, preclinical investigations should focus on aversive memories resulting in maladaptive outcomes and consider sex-related differences to enhance their translatability. After selecting a relatively high training magnitude leading to the formation of a more intense and generalized fear memory in adult female and male rats, we investigated whether two clinically approved drugs disrupting its reconsolidation remain effective. We found resistant reconsolidation impairment by the α2-adrenergic receptor agonist clonidine or cannabidiol, a major non-psychotomimetic Cannabis sativa component. However, pre-retrieval administration of D-cycloserine, a partial agonist at the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex, facilitated their impairing effects on reconsolidation. A similar reconsolidation blockade by clonidine or cannabidiol was achieved following exposure to a non-conditioned but generalized context after D-cycloserine administration. This suggests that sufficient memory destabilization can accompany generalized fear expression. Combining clonidine with cannabidiol without potentiating memory destabilization by D-cycloserine was ineffective. These findings highlight the importance of NMDA receptor signaling in memory destabilization and underscore the efficacy of a dual-step pharmacological intervention in attenuating traumatic-like memories, even in a context different from the original learning environment.

Blockade of D-serine signaling and adult hippocampal neurogenesis attenuates remote contextual fear memory following multiple memory retrievals in male mice.

The retrieval of fear memories induces two opposing processes, reconsolidation, and extinction. The memory reconsolidation is an active process that involves gene expression and updates an existing memory. It is hypothesized that blockade of reconsolidation by manipulating the neurobiological factors, which are mechanistically involved in the process, could weaken or disrupt the original fear memory. The N-methyl-D-aspartate (NMDA) receptor and hippocampal neurogenesis play crucial roles in hippocampus-dependent memory processes, including reconsolidation. Using contextual fear conditioning paradigm with multiple retrievals, we attempted to weaken the original contextual fear memory by repeatedly disrupting retrieval-induced reconsolidation via downregulation of NMDA receptor signaling and inhibition of neurogenesis. In the first experiment, prior to fear conditioning, NMDA receptor signaling was downregulated by the genetic reduction of its co-agonist, D-serine, and the neurogenesis was dampened by focal X-ray irradiation on the hippocampus. We found that simultaneous D-serine reduction and neurogenesis dampening resulted in a progressive decrease in freezing following each retrieval, leading to an attenuation of remote contextual fear memory on day 28. In the second experiment using the same behavioral protocols, after conditioning, pharmacological approaches were conducted to simultaneously block D-serine signaling and neurogenesis, resulting in a similar suppressive effect on the remote fear memory. The present findings provide insights for understanding the role of D-serine-mediated NMDA receptor signaling and neurogenesis in memory retrieval and the maintenance of remote fear memory, and improving the efficacy of exposure-based therapy for the treatment of post-traumatic stress disorder (PTSD).

A narrative review of the epigenetics of post-traumatic stress disorder and post-traumatic stress disorder treatment.

Epigenetic research in post-traumatic stress disorder (PTSD) is essential, given that environmental stressors and fear play such a crucial role in its development. As such, it may provide a framework for understanding individual differences in the prevalence of the disorder and in treatment response. This paper reviews the epigenetic markers associated with PTSD and its treatment, including candidate genes and epigenome-wide studies. Because the etiopathogenesis of PTSD rests heavily on learning and memory, we also draw upon animal neuroepigenetic research on the acquisition, update and erasure of fear memory, focusing on the mechanisms associated with memory reconsolidation. Reconsolidation blockade (or impairment) treatment in PTSD has been studied in clinical trials and, from a neurological perspective, may hold promise for identifying epigenetic markers of successful therapy. We conclude this paper by discussing several key considerations and challenges in epigenetic research on PTSD in humans.

Targeting neuronal nitric oxide synthase and the nitrergic system in post-traumatic stress disorder

Current pharmacological approaches to treatment of post-traumatic stress disorder (PTSD) lack adequate effectiveness. As a result, identifying new molecular targets for drug development is necessary. Furthermore, fear learning and memory in PTSD can undergo different phases, such as fear acquisition, consolidation, and extinction. Each phase may involve different cellular pathways and brain regions. As a result, effective management of PTSD requires mindfulness of the timing of drug administration. One of the molecular targets currently under intense investigation is the N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR). However, despite the therapeutic efficacy of drugs targeting NMDAR, their translation into clinical use has been challenging due to their various side effects. One possible solution to this problem is to target signaling proteins downstream to NMDAR to improve targeting specificity. One of these proteins is the neuronal nitric oxide synthase (nNOS), which is activated following calcium influx through the NMDAR. In this paper, we review the literature on the pharmacological modulation of nNOS in animal models of PTSD to evaluate its therapeutic potential. Furthermore, we attempt to decipher the inconsistencies observed between the findings of these studies based on the specific phase of fear learning which they had targeted. Inhibition of nNOS may inhibit fear acquisition and recall, while not having a significant effect on fear consolidation and extinction. However, it may improve extinction consolidation or reconsolidation blockade. Modulation of nNOS has therapeutic potential against PTSD and warrants further development for use in the clinical setting.

Lack of Effect of Propranolol on the Reconsolidation of Conditioned Fear Memory due to a Failure to Engage Memory Destabilisation

The prospect of exploiting memory reconsolidation to treat mental health disorders has received great research interest, particularly following demonstrations that the β-adrenergic receptor antagonist propranolol, which is safe for use in humans, can disrupt the reconsolidation of pavlovian conditioned fear memories. However, recent studies have failed to replicate the effects of propranolol on fear memory reconsolidation, and have questioned whether treatments based upon reconsolidation blockade would be robust enough for clinical translation. It remains possible, though, that studies reporting no effect of propranolol on memory reconsolidation could be due to a failure to engage the memory destabilisation process, which is necessary for the memory to become susceptible to disruption with amnestic agents. Demonstrating that memory destabilisation has not been engaged is challenging when only using behavioural measures, but there are molecular correlates of memory destabilisation that can be used to determine whether memory lability has been induced. Here, we attempted to replicate the classic finding that systemic administration of propranolol disrupts the reconsolidation of a pavlovian auditory fear memory. Following a failure to replicate, we manipulated the parameters of the memory reactivation session to enhance prediction error in an attempt to overcome the boundary conditions of reconsolidation. On finding no disruption of memory despite these manipulations, we examined the expression of the post-synaptic density protein Shank in the basolateral amygdala. Degradation of Shank has been shown to correlate with the induction of memory lability, but we found no effect on Shank expression, consistent with the lack of observed behavioural effects.

Generalization and recovery of post-retrieval amnesia.

Selective amnesia for previously established memories can be induced by administering drugs that impair protein synthesis shortly after memory reactivation. Competing theoretical accounts attribute this selective post-retrieval amnesia to drug-induced engram degradation (reconsolidation blockade) or to incorporation of sensory features of the reactivation experience into the memory representation, hampering later retrieval in a drug-free state (memory integration). Here we present evidence that critically challenges both accounts. In contextual fear conditioning in rats, we find that amnesia induced by administration of midazolam (MDZ) after reexposure to the training context A generalizes readily to a similar context B. Amnesia is also observed when animals are exposed to the similar context B prior to MDZ administration and later tested for fear to context B but recovers when instead testing for fear to the original training context A or an equally similar but novel context C. Next to their theoretical implications for the nature of forgetting, our findings raise important questions about the viability of reconsolidation-based interventions for the treatment of emotional disorders. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

An assessment of rapamycin for weakening binge-eating memories via reconsolidation: a pre-registered, double-blind randomised placebo-controlled experimental study.

Maladaptive learning linking environmental food cues to high-palatability food reward plays a central role in overconsumption in obesity and binge eating disorders. The process of memory reconsolidation offers a mechanism to weaken such learning, potentially ameliorating over-eating behaviour. Here we investigated whether putatively interfering with synaptic plasticity using the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, could weaken retrieved chocolate reward memories through blockade of reconsolidation. Seventy five healthy volunteers with a tendency to binge eat chocolate were randomised to retrieve chocolate reward memory under 10 mg rapamycin (RET + RAP, active condition), or placebo (RET + PBO), or they received 10 mg rapamycin without subsequent retrieval (NO RET + RAP). Indices of chocolate reward memory strength were assessed one week pre and post manipulation and at one month follow-up. Contrary to hypotheses, the RET + RAP group did not show any greater reduction than control groups on indices of motivational salience of chocolate cues, motivation to consume chocolate or liking of chocolate. Mild evidence of improvement in the RET + RAP group was found, but this was limited to reduced chocolate binge episodes and improved healthy food choices. We did not find convincing evidence of comprehensive naturalistic chocolate reward memory reconsolidation blockade by rapamycin. The effects on chocolate bingeing and food choices may warrant further investigation. These limited positive findings may be attributable to insufficient interference with mTOR signalling with 10 mg rapamycin, or failure to destabilise chocolate memories during retrieval.

Cannabidiol and the Remainder of the Plant Extract Modulate the Effects of Δ9-Tetrahydrocannabinol on Fear Memory Reconsolidation.

Background: Δ9-Tetrahydrocannabinol (THC, a CB1 receptor agonist) and Cannabidiol (CBD, a non-competitive antagonist of endogenous CB1 and CB2 ligands) are two primary components of Cannabis species, and may modulate fear learning in mammals. The CB1 receptor is widely distributed throughout the cortex and some limbic regions typically associated with fear learning. Humans with posttraumatic disorder (PTSD) have widespread upregulation of CB1 receptor density and reduced availability of endogenous cannabinoid anandamide, suggesting a role for the endocannabinoid system in PTSD. Pharmacological blockade of memory reconsolidation following recall of a conditioned response modulates the expression of learned fear and may represent a viable target for the development of new treatments for PTSD. In this study, we focused on assessing the impact of the key compounds of the marijuana plant both singly and, more importantly, in concert on attenuation of learned fear. Specifically, we assessed the impact of THC, CBD, and/or the remaining plant materials (post-extraction; background material), on reconsolidation of learned fear.Method: Male Sprague-Dawley rats received six 1.0 mA continuous foot shocks (contextual training). Twenty-four hours later, rats were re-exposed to the context. Immediately following memory retrieval (recall) rats received oral administration of low dose THC, high dose THC, CBD, CBD + low THC, CBD + high THC [as isolated phytochemicals and, in separate experiments, in combination with plant background material (BM)]. Rodents were tested for freezing response context re-exposure at 24 h and 7 days following training.Results: CBD alone, but not THC alone, significantly attenuated fear memory reconsolidation when administered immediately after recall. The effect persisted for at least 7 days. A combination of CBD and THC also attenuated the fear response. Plant BM also significantly attenuated reconsolidation of learned fear both on its own and in combination with THC and CBD. Finally, THC attenuated reconsolidation of learned fear only when co-administered with CBD or plant BM.Conclusion: CBD may provide a novel treatment strategy for targeting fear-memories. Furthermore, plant BM also significantly attenuated the fear response. However, whereas THC alone had no significant effects, its effects were modulated by the addition of other compounds. Future research should investigate some of the other components present in the plant BM (such as terpenes) for their effects alone, or in combination with isolated pure cannabinoids, on fear learning.

Post Traumatic Stress Disorder and Substance Use Disorder as Two Pathologies Affecting Memory Reactivation: Implications for New Therapeutic Approaches.

In the present review, we provide evidence indicating that although post traumatic stress disorder (PTSD) and substance use disorder (SUD) are two distinct pathologies with very different impacts on people affected by these chronic illnesses, they share numerous common characteristics, present high rates of co-morbidity, and may result from common physiological dysfunctions. We propose that these pathologies result from hyper reactivity to reminders, and thus should be considered as two disorders of memory, treated as such. We review the different possibilities to intervene on pathological memories such as extinction therapy and reconsolidation blockade. We also introduce new therapeutic avenues directly indicate by our recent proposal to replace the consolidation/reconsolidation hypothesis by the integration concept. State dependency and emotional remodeling are two innovative treatments that have already provided encouraging results. In summary, this review shows that the discovery of reactivation-dependent memory malleability has open new therapeutic avenues based on the reprocessing of pathological memories, which constitute promising approaches to treat PTSD and SUD.

Stimulation of Peroxisome Proliferator-Activated Receptor-α by N-Palmitoylethanolamine Engages Allopregnanolone Biosynthesis to Modulate Emotional Behavior

BackgroundThe endocannabinoid and neurosteroid systems regulate emotions and stress responses. Activation of peroxisome proliferator-activated receptor (PPAR)-α by the endocannabinoid congener N-palmitoylethanolamine (PEA) regulates pathophysiological systems (e.g., inflammation, oxidative stress) and induces peripheral biosynthesis of allopregnanolone, a gamma-aminobutyric acidergic neurosteroid implicated in mood disorders. However, effects of PPAR-α on emotional behavior are poorly understood. MethodsWe studied the impact of PPAR-α activation on emotional behavior in a mouse model of posttraumatic stress disorder. Neurosteroid levels before and after PEA treatment were measured by gas chromatography–mass spectrometry in relevant brain regions of socially isolated versus group-housed mice exposed to the contextual fear conditioning test, elevated plus maze test, forced swim test, and tail suspension test. Neurosteroidogenic enzyme levels were quantified in hippocampus by Western blot. ResultsPEA administered in a model of conditioned contextual fear reconsolidation blockade facilitated fear extinction and fear extinction retention and induced marked antidepressive- and anxiolytic-like effects in socially isolated mice with reduced brain allopregnanolone levels. These effects were mimicked by the PPAR-α synthetic agonists, fenofibrate and GW7647, and were prevented by PPAR-α deletion, PPAR-α antagonists, and neurosteroid-enzyme inhibitors. Behavioral improvements correlated with PEA-induced upregulation of PPAR-α, neurosteroidogenic enzyme expression, and normalization of corticolimbic allopregnanolone levels. ConclusionsThis evidence supports a previously unknown role for PPAR-α in behavior regulation and suggests new strategies for the treatment of neuropsychopathologies characterized by deficient neurosteroidogenesis, including posttraumatic stress disorder and major depressive disorder.

Different temporal windows for CB1 receptor involvement in contextual fear memory destabilisation in the amygdala and hippocampus.

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.

Blockade of aversive and appetitive memory reconsolidation by systemic administration of beta-noradrenergic and NMDA-receptors antagonists

Blockade of aversive and appetitive memory reconsolidation by systemic administration of beta-noradrenergic and NMDA-receptors antagonists

Reconsolidation blockade for the treatment of addiction: challenges, new targets, and opportunities

Addiction is a chronic, relapsing disorder. The progression to pathological drug-seeking is thought to be driven by maladaptive learning processes which store and maintain associative memory, linking drug highs with cues and actions in the environment. These memories can encode Pavlovian associations which link predictive stimuli (e.g., people, places, and paraphernalia) with a hedonic drug high, as well as instrumental learning about the actions required to obtain drug-associated incentives. Learned memories are not permanent however, and much recent interest has been generated in exploiting the process of reconsolidation to erase or significantly weaken maladaptive memories to treat several mental health disorders, including addictions. Normally reconsolidation serves to update and maintain the adaptive relevance of memories, however administration of amnestic agents within the critical “reconsolidation window” can weaken or even erase maladaptive memories. Here we discuss recent advances in the field, including ongoing efforts to translate preclinical reconsolidation research in animal models into clinical practice.

Propranolol Combined With Reactivation Therapy May Reduce PTSD Symptoms

Back to table of contents Previous article Next article PsychopharmacologyFull AccessPropranolol Combined With Reactivation Therapy May Reduce PTSD SymptomsNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:2 Feb 2018https://doi.org/10.1176/appi.pn.2018.pp2a2AbstractPropranolol may interfere with the reconsolidation of traumatic memories brought forth during the reactivation session, thus making them less potent and fear-inducing.It would be a tremendous breakthrough in treating posttraumatic stress disorder (PTSD) if patients were able to rid themselves of unwanted traumatic memories. Researchers and clinicians once believed that weakening memories might be an impossible task; however, studies over the past decade have found that when stored memories are retrieved, or reactivated, they temporarily enter a malleable state. Once a person stops thinking about a memory, the memory returns to a stable form, a process known as reconsolidation. iStock/laflorA drug that interferes with the reconsolidation of a reactivated traumatic memory could potentially weaken or even erase the retrieved memory. A study published January 12 in AJP in Advance suggests that the beta-blocker propranolol might be able to block memory reconsolidation.Adults with PTSD who actively recalled their traumatic event under the influence of propranolol once a week, for up to six weeks, reported a substantial decrease in PTSD symptoms compared with participants who took placebo. This decrease was evident from both the perspective of the patient and clinician.“The effect sizes obtained for pre-reactivation propranolol in our study compare well to those obtained with the best evidence-based treatment for PTSD, namely, cognitive-behavioral therapy, as well as those obtained with the most recommended pharmacological treatment for PTSD, namely, SSRIs,” Alain Brunet, Ph.D., an associate professor of psychiatry at McGill University in Montreal, and colleagues wrote. “Should these results be replicated in further studies, propranolol blockade of reconsolidation may become a new therapy for some patients with PTSD.”At the start of the six-week, double-blind, randomized trial, adults who had experienced at least six months of PTSD symptoms were assigned to take either propranolol (administered as 0.67 mg/kg of short-acting propranolol plus 1.0 mg/kg of long-acting propranolol) or placebo one hour before a brief memory reactivation session.Patients were excluded from the trial if they had a basal systolic blood pressure <100 mmHg; a basal heart rate <55 beats per minute; a medical condition contraindicating administration of propranolol or potentially confounding the results, such as arrhythmia or congestive heart failure; or were currently using medication that may interact adversely with propranolol, such as antiarrhythmic medications or calcium channel blockers. Three people in each group reported side effects after receiving the placebo or propranolol and were excluded from the rest of the trial.During the reactivation session, the participants were asked to write a one-page trauma narrative, focusing on the most disturbing moments of the traumatic event and including five or more bodily sensations drawn from a checklist. The participants were then asked to read the narrative aloud once to the therapist “as if they were back in the event.” At subsequent weekly visits, participants again took propranolol or placebo and were asked to re-read the narrative 90 minutes after they took their medicine.The participants filled out the patient-rated PTSD Checklist Specific (PCL-S) scale at the beginning of each treatment session, before propranolol or placebo was administered. The Clinician-Administered PTSD Scale (CAPS) was also used one week before and one week after the six-week trial.Both the propranolol and placebo groups had similar PCL-S and CAPS scores at baseline. At the end of the study participants who took propranolol had greater decreases in both measurements that were statistically significant. Pre- to post-treatment CAPS improvements were 38 percent in the propranolol group and 24 percent in the placebo group, while PCL-S improvements were 56 percent in the propranolol group and 15 percent in the placebo group. The investigators also conducted a six-month follow-up and found that the participants in the propranolol group continued to experience lower symptom scores than the placebo group, even without continued use of propranolol. However, the authors noted that the follow-up data only included 14 participants. “Further studies should make efforts to retain a greater percentage of participants for long-term follow-up,” the authors wrote.The patients in this study underwent trauma reactivation but did not receive full exposure therapy. Exposure therapy is a commonly used PTSD treatment that seeks to extinguish the link between a memory and the negative behaviors it elicits. While both therapies involve coaching the patient to relive a past traumatic event in some manner, the exposure component of reconsolidation therapy is kept to a maximum of about 25 minutes. This study was supported by a grant from the U.S. Army Congressionally Directed Medical Research Program. ■Back to Psychopharmacology Newsletter Table of Contents ISSUES NewArchived

The metaplastic effects of NMDA receptors blockade on reactivation of instrumental memories in rats.

Metaplasticity, defined as the plasticity of synaptic plasticity, could affect learning and memory at different neural levels. It was hypothesized that metaplasticity changes on glutamate receptors may affect memory destabilization, promoting or preventing reconsolidation. We investigated the metaplastic effect of NMDA channel blocker MK-801 on sucrose instrumental memory reconsolidation in a behavioural rat model associated to the assessment of molecular markers of metaplasticity, memory retrieval, destabilization and reconsolidation. Following instrumental conditioning and forced abstinence, rats were intraperitoneally treated with MK-801 or vehicle 24 h before the exposure to memory retrieval or not-retrieval. Separate groups were tested for in-vivo extinction of responding (24 h and 7 d after reactivation) or ex-vivo assessment of transcription factor Zif268 and ribosomal protein rpS6 phosphorylation in nucleus accumbens (NAc) and amygdala (Amy). MK-801 significantly inhibited instrumental responding at extinction test, suggesting reconsolidation blockade of instrumental memory. The decrease of Zif268 and phosphorylated-rpS6 levels in NAc and Amy in MK-801/Retrieval vs. Vehicle/Retrieval group supported the behavioural findings. An increase of GluN2B, GluA1 and mGluR5 in NAc, and GluN2B in Amy, 24 h after MK-801 indicated the trigger of associated metaplastic changes. Our findings show that metaplastic changes induced by NMDA receptors blockade affected sucrose instrumental memory retrieval as shown by both behavioural and molecular changes. We hypothesize that these findings however suggested a switch to extinction rather than a reconsolidation.

Evaluation of the reconsolidation of traumatic memories protocol for the treatment of PTSD: a randomized, wait-list-controlled trial

Introduction: The reconsolidation of traumatic memories (RTM) is a cognitive intervention for post-traumatic stress disorder (PTSD) believed to employ reconsolidation blockade with significant potential as a cost-effective and empirically supported treatment. This is the second empirical evaluation of the intervention. Methods: This study used a randomized wait-list-controlled design ( n=30) to examine the efficacy of three sessions of RTM among male Veterans having high symptom scores on the PTSD Symptom Scale Interview (PSS-I) and the PTSD Checklist – military version (PCL-M) with current-month flashbacks and nightmares. Of the 55 volunteers, 30 met inclusion criteria and participated in the study, 15 each were randomly assigned to treatment and control conditions. After completing a six-week wait period, control subjects also received the intervention. Results: Data analyses suggest that RTM was superior to control. There were significant pre-post treatment improvements across measures of PTSD. Gains were maintained at 6 and 12-month follow-ups. At six months post, within group RTM effect sizes (Hedges' g) ranged from 2.79 to 5.33. Further, at six months post, 88% of those treated had lost the DSM diagnosis for PTSD: 15% had lost DSM diagnosis (CPL-M&lt;50 and DSM criteria not met) and 73% were in complete remission from all symptoms (PCL-M&lt;30). Therapist competence and adherence to treatment protocols were both strong. Patient satisfaction with the intervention was high. Discussion: Study limitations and implications for the assessment and treatment of Veterans with PTSD are discussed.

Role of protein synthesis and DNA methylation in the consolidation and maintenance of long-term memory in Aplysia.

Previously, we reported that long-term memory (LTM) in Aplysia can be reinstated by truncated (partial) training following its disruption by reconsolidation blockade and inhibition of PKM (Chen et al., 2014). Here, we report that LTM can be induced by partial training after disruption of original consolidation by protein synthesis inhibition (PSI) begun shortly after training. But when PSI occurs during training, partial training cannot subsequently establish LTM. Furthermore, we find that inhibition of DNA methyltransferase (DNMT), whether during training or shortly afterwards, blocks consolidation of LTM and prevents its subsequent induction by truncated training; moreover, later inhibition of DNMT eliminates consolidated LTM. Thus, the consolidation of LTM depends on two functionally distinct phases of protein synthesis: an early phase that appears to prime LTM; and a later phase whose successful completion is necessary for the normal expression of LTM. Both the consolidation and maintenance of LTM depend on DNA methylation.

The chains of habits: too strong to be broken by reconsolidation blockade?

Memory reconsolidation — the process by which memories can become destabilised at retrieval, and be updated or modified — offers a potential therapeutic opportunity for mental health disorders based upon maladaptive emotional memories, such as drug addiction. Blocking the reconsolidation of pavlovian cue-drug memories persistently reduces subsequent relapse in rodent models and in human experimental medicine studies, but little is known about whether instrumental drug-seeking memories can be disrupted, particularly when individuals have transitioned to a compulsive drug-seeking habit. Here we discuss how studies of drug memory reconsolidation can be made more translationally relevant, with particular attention to the challenges faced by those attempting to disrupt the reconsolidation of habit memories.

Effect of a positive reinforcing stimulus on fear memory reconsolidation in ethanol withdrawn rats: Influence of d-cycloserine

The pharmacological blockade of memory reconsolidation has been suggested as a potential treatment to the attenuation of maladaptive memories associated to psychiatric disorders and drug addiction. To interfere with the process of fear memory reconsolidation using a manipulation safer than pharmacological interventions, here we examined whether a positive reinforcing stimulus (non-alcoholic beer, NB) post-memory retrieval can decrease the fear response in ethanol withdrawn (ETOH) animals. We first evaluated the potential interfering effect of NB on memory reconsolidation in non-ethanol dependent (control, CON) rats. Non-alcoholic beer intake shortly after memory retrieval attenuated the fear response in CON rats. A resistance to destabilization/reconsolidation process was previously observed in ETOH rats, which was reversed by the activation of NMDA receptor induced by pre-retrieval d-cycloserine (DCS) administration. Therefore, the influence of DCS (5mg/kg; i.p.) to facilitate the disruptive effect of NB on fear memory was examined in ETOH animals. As expected, NB was ineffective to attenuate the fear response in ETOH rats, with DCS being necessary to promote the disruptive effect of NB on the reconsolidation in these animals. Hence, DCS/reinforcing stimulus in combination with memory reactivation can be considered as an alternative approach for disrupting resistant fear memories.