Abstract
RationalePharmacological 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.ObjectivesHere, we aimed to determine the functional involvement of dopamine D1 receptors in cued fear memory destabilisation, using systemic drug administration.ResultsWe 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.ConclusionsThe use of combination pharmacological treatment to stimulate memory destabilisation and impair reconsolidation has potential therapeutic benefits, without risking a maladaptive increase of fear.
Highlights
The disruption of memory reconsolidation, the restabilisation of a memory destabilised following retrieval, represents a promising therapeutic approach for anxiety and traumarelated disorders
While the efficacy of reconsolidation impairment appears relatively robust, targeting reconsolidation depends upon the success of destabilising the memory behaviourally via a memory reactivation session, which usually takes the form of cue re-exposure (Almeida-Correa and Amaral 2014)
The disruptive effect of mifepristone was not replicated with stronger conditioning (1.0-s, 0.4-mA footshock, Fig. 1c,d)
Summary
The disruption of memory reconsolidation, the restabilisation of a memory destabilised following retrieval, represents a promising therapeutic approach for anxiety and traumarelated disorders. While the efficacy of reconsolidation impairment appears relatively robust, targeting reconsolidation depends upon the success of destabilising the memory behaviourally via a memory reactivation session, which usually takes the form of cue re-exposure (Almeida-Correa and Amaral 2014). It is increasingly evident that successful reconsolidation impairment is far from guaranteed (Kindt and van Emmerik 2016), especially as there are unpredictable boundary conditions that govern memory destabilisation (Wideman et al 2018). We recently demonstrated that there appears to be no reliable basis upon which to predict the behavioural parameters that will trigger memory destabilisation/reconsolidation (Cassini et al 2017). Lack of replicability of reconsolidation impairments may well be due to poorly understood boundary conditions on memory destabilisation (Bos et al 2014)
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