Preclinical Assessment for Selectively Disrupting a Traumatic Memory via Postretrieval Inhibition of Glucocorticoid Receptors

Taubenfeld, Stephen M.; Riceberg, Justin S.; New, Antonia S.; Alberini, Cristina M.

doi:10.1016/j.biopsych.2008.07.005

Cited by 66 publications

(66 citation statements)

References 74 publications

(77 reference statements)

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“…Our results are consistent with several studies investigating reconsolidation blockers either systemically (Debiec and Ledoux, 2004;Blundell et al, 2008;Taubenfeld et al, 2009;Pitman et al, 2011) or intracranially (Nader et al, 2000;Debiec and Ledoux, 2004;Ben Mamou et al, 2006;Jin et al, 2007). Indeed, it is accepted in the literature that the lack of spontaneous recovery, the selectivity to reactivated memories, and the presence of intact short-term memory are criteria that define the reconsolidation process.…”

Section: Reconsolidation Specificitysupporting

confidence: 92%

Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

Pitman¹,

Bolshakov²,

Brunet³

et al. 2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERMassachusetts General Hospital, Boston, MA, 02114 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES Note: The previous report was deemed unacceptable for the following reason. "There is no data in the body of this report and data in the appended manuscript are not cited in the body of the report to support key research accomplishments. In a revised report, please summarize the data from the previous year. The appended publication can be used as supporting material as long as figures are referenced in the body of the progress report." The following revised report now contains data in the body of the report, which are indicated by yellow highlighting.14. ABSTRACT-The aim of this project is to develop post-reactivation (PR) pharmacologic interventions that may serve as novel treatments for posttraumatic stress disorder (PTSD). The underlying theory is that candidate drugs, when given following the reactivation of a conditioned fear response in animals, or a traumatic memory in humans, will reduce the strength of the conditioned response or traumatic memory. We plan to test such drugs, either alone or in combination, for their possible reconsolidation-blocking properties in a hierarchy of experiments. Drugs that show promise at a given stage of investigation will be advanced to the next stage. In Stage I, we will evaluate the ability of candidate drugs to reduce freezing in a Pavlovian cue-conditioned fear task in rats. In Stage II, we will evaluate the ability of candidate drugs to reverse fear conditioning-induced synaptic enhancement in rat amygdala slices using whole-cell electrophysiologic recording. In Stage III, we will test the ability of a single session of PR candidate drug to reduce subsequent psychophysiologic responding during script-driven imagery of the traumatic event in trauma-exposed human subjects. In Stage IV, we will test the ability of a series of PR candidate drug therapy sessions to reduce symptoms in PTSD patients.

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Section: Reconsolidation Specificitysupporting

confidence: 92%

Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

Pitman¹,

Bolshakov²,

Brunet³

et al. 2012

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“…These data strongly suggest that the experience of a traumatic event before fear acquisition strengthens fear memory formation and attenuates the degree of memory instability after retrieval (which becomes more evident in older memories). In support of the view that stronger memories are less vulnerable to disruption after recall, several authors showed that the increase in the number of footshock trials during fear acquisition produces a memory trace that is more resistant to interference after reactivation (Suzuki et al, 2004;Taubenfeld et al, 2009;Wang et al, 2009). It is widely accepted that several conditions constrain the occurrence of reactivation-induced instability and the subsequent development of memory reconsolidation.…”

Section: Discussionmentioning

confidence: 99%

Previous Stress Attenuates the Susceptibility to Midazolam's Disruptive Effect on Fear Memory Reconsolidation: Influence of Pre-Reactivation D-Cycloserine Administration

Bustos

Giachero

Maldonado

et al. 2009

Neuropsychopharmacol

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It is well known that, under certain boundary conditions, the retrieval of a stable consolidated memory results into a labile one. During this unstable phase, memory can be vulnerable to interference by a number of pharmacological agents, including benzodiazepines. One of the goals of this study was to evaluate the vulnerability to midazolam (MDZ) after reactivation of recent and remote contextual fear memories in animals that experienced a stressful situation before learning. Animals were subjected to a restraint session and trained in a contextual fear paradigm the following day; consolidated memories were reactivated at different times after learning and different MDZ doses (1.5, 3.0 mg/kg) were administered to rats after reactivation. Our results show that MDZ did not affect memory reconsolidation in older-than-one-day memories of stressed animals, even after the administration of a higher MDZ dose and a longer reactivation session (5 min). In contrast, MDZ was effective in blocking reconsolidation at all memory ages in unstressed animals. In addition, the current research investigated whether activating NMDA sites before reactivation promotes the destabilization of resistant memories such as those of stressed animals. We tested the influence of pre-reactivation D-cycloserine (DCS), a partial NMDA agonist, on MDZ's effect on fear memory reconsolidation in stressed animals. Our findings indicate that DCS before reactivation promotes retrieval-induced lability in resistant memory traces, as MDZ-induced memory impairment in stressed rats became evident with pre-reactivation DCS but not after pre-reactivation sterile isotonic saline.

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“…Interfering with the reconsolidation process provides an opportunity for disrupting memories that may contribute to the development of psychiatric disorders such as post-traumatic stress disorder (PTSD) or addiction (Dudai 2006;Diergaarde et al 2008;Taylor et al 2009). Recently, several pharmacological compounds have been tested in animal models of fear learning in order to identify drugs that can be potentially relevant for clinical trials of trauma-induced pathologies and, in particular, PTSD (Debiec and LeDoux 2006;Brunet et al 2008;Taubenfeld et al 2008). Particular attention has been given to blockers of stress hormones, including antagonists of glucocorticoid or b-adrenergic receptors.…”

mentioning

confidence: 99%

“…We previously reported that the glucocorticoid receptor antagonist RU38486 persistently disrupts inhibitory avoidance (IA) memory retention if administered either in the amygdala or systemically immediately following retrieval (Tronel and Alberini 2007;Taubenfeld et al 2008). Thus, we were interested in investigating the potential synergistic effect of blocking both glucocorticoid and b-adrenergic receptors.…”

mentioning

confidence: 99%

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Limited efficacy of propranolol on the reconsolidation of fear memories

Muravieva¹,

Alberini²

2010

Learn. Mem.

Self Cite

117

113

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Previous studies suggested that the b-adrenergic receptor antagonist propranolol might be a novel, potential treatment for post-traumatic stress disorder (PTSD). This hypothesis stemmed mainly from rodent studies showing that propranolol interferes with the reconsolidation of Pavlovian fear conditioning (FC). However, subsequent investigations in humans have produced controversial evidence about the effect of propranolol on fear memories and an effect on PTSD symptomatology has yet to be reported. Thus, it remains to be established whether propranolol interferes with the reconsolidation of fear memories at large. To address this question, we tested the effect of systemic injections of propranolol administered before or after the retrieval of an inhibitory avoidance (IA) memory elicited with different footshock intensities. In parallel, the same treatment was tested on the reconsolidation of Pavlovian FC. Propranolol showed no effect on the reconsolidation of IA, although the pre-retrieval administration resulted in a significant retrieval impairment. This impairment was transient, and memory returned to control levels at later times. In agreement with previous studies, we found that systemic administration of propranolol disrupts the reconsolidation of Pavlovian FC and that its injection following a retrieval elicited by cue exposure also interferes with the reconsolidation of contextual FC. Hence, propranolol disrupts the reconsolidation of Pavlovian FC, but has no effect on the reconsolidation of IA. The results indicate that the efficacy of systemic administration of propranol in disrupting the reconsolidation of fear memories is limited.

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Preclinical Assessment for Selectively Disrupting a Traumatic Memory via Postretrieval Inhibition of Glucocorticoid Receptors

Cited by 66 publications

References 74 publications

Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

Previous Stress Attenuates the Susceptibility to Midazolam's Disruptive Effect on Fear Memory Reconsolidation: Influence of Pre-Reactivation D-Cycloserine Administration

Limited efficacy of propranolol on the reconsolidation of fear memories

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