Drug memory reconsolidation: from molecular mechanisms to the clinical context

Abstract

Since its rediscovery at the beginning of the 21st 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.

Rethinking Memory Impairments: Retrieval Failure

“…Since the seminal findings of Nader and coworkers regarding the neural basis of pharmacologically-induced, cue-dependent memory malleability at the turn of this century, abundant empirical evidence has been widely interpreted as suggesting that post-retrieval attenuation of conditioned responding indicates that memories can undergo destabilization and reconsolidation. This opens up the possibility that memory reconsolidation represents a unique possibility for long-term intervention of maladaptive memories and suggests neurobiologically plausible mechanisms that might underlie cue-dependent memory malleability (e.g., for reviews, see Milton, 2023;Phelps & Hofmann, 2019). Consequently, research using different species (e.g., planaria, crabs, fish, slugs, chicks, rodents, and humans), tasks (e.g., appetitively and aversively motivated), and using different post-retrieval pharmacological (e.g., anisomycin, propranolol, midazolam) and non-pharmacological manipulations (e.g., conducting…”

“…Undoubtedly, the observation that disruption of consolidation and also that presumably consolidated memories can be returned to an unstable and active state through memory reactivation and become susceptible to amnesics that diminish memory performance in nonhumans (e.g., Misanin, Miller & Lewis, 1968;Nader, Schafe, & Ledoux, 2000), led to the thought that a similar approach would be helpful in clinical situations with humans. This raised hopes for developing treatments for anxiety, posttraumatic stress disorder, and substance abuse disorders (e.g., for reviews, see Milton, 2023;Lee, Nader, & Schiller, 2017;Walsh, Das, Saladin, & Kamboj, 2018). The increased emphasis on the attenuation of memory expression is, however, far from a new development of this century; instead, it has a long and interesting history shared by the domains of experimental psychology and (more recently) behavioural neuroscience.…”

Transcriptional analysis of neuronal ensembles of alcohol memories within the nucleus accumbens

“…Relapse is often caused by cue-induced craving, where an alcohol-associated cue evokes strong craving and relapse even after protracted abstinence. Therefore, disruption of the memory for the cue-alcohol association is expected to reduce or even prevent relapse [3][4][5][6] .…”