Dopaminergic D1 receptor signalling is necessary, but not sufficient for cued fear memory destabilisation

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.

Memory destabilization during reconsolidation – A consequence of homeostatic plasticity?

“…Detection of mismatch/prediction error within memory-encoding areas could thus be implemented both by novelty signals sent by other brain structures (such as the ventral tegmental area) and by internal network dynamics (as occurs in our model). Support for this view comes from the asymmetry in the necessity and sufficiency of destabilization mechanisms: while dopamine D1 receptors are necessary for fear memory destabilization, for instance (Flavell and Lee, 2019; Merlo et al, 2015), their activation is not sufficient to induce it (Flavell and Lee, 2019). Thus, it is possible that multiple processes are necessary for successful memory destabilization, including an interaction between dopaminergic signaling and local network plasticity.…”

A novel role for cortical acetylcholine in object memory updating

“…Prediction error and other forms of salient novelty at the time of memory reactivation are strongly implicated in memory destabilization under certain conditions 40,41 , perhaps to signal the opportunity for memory updating. In addition to past work implicating ACh in novelty-regulated memory destabilization, there appears to be a strong role for dopamine in responding to prediction error in various reconsolidation paradigms [42][43][44][45] . Thus, further investigation is required to delineate the specific roles of various neurotransmitter systems in memory destabilization and modification; the PROMM task should prove highly valuable for such studies.…”

Dopamine regulation of contextual fear and associated neural circuit function

“…Another possibility is to use dopaminergic drugs to target destabilization of the fear memory trace, such that the memory is weakened or updated to reduce or possibly even remove its aversive association before it is then reconsolidated in its modified form. While MPTP or D1‐like receptor blockade was found to have no effect on the reconsolidation of contextual fear memory (Heath et al., 2015; Kinoshita et al., 2015), studies have shown that dopamine and D1‐like receptor signalling play a role in the destabilization of other types of memory and allow for their disruption via the subsequent pharmacological impairment of reconsolidation (Flavell & Lee, 2019; Merlo et al., 2015; Reichelt, Exton‐McGuinness, & Lee, 2013; Rossato et al., 2014). Understanding how dopamine regulates memory destabilization is particularly relevant to trauma‐related memories given that strong or persistent memories are thought to be resistant to disruption by reconsolidation impairment (Lee, 2009).…”