Reconsolidation and Memory Interference Toolkit (REMIT): Identifying how to destabilise and overwrite maladaptive alcohol memories.

Alcohol Use Disorder (AUD) is a global disease challenge which incurs vast health and social costs. Current treatments fail in the long term as they do not address the aberrant memory processes that maintain drinkers' susceptibility to relapse even after years of abstinence. This quiescent susceptibility is due to Maladaptive Motivational Memories (MMMs) that accompany and support alcohol abuse. Associations formed between environmental 'cues' and drinking imbue the cues with motivational properties that cause cravings, alcohol seeking and relapse when similar cues are re-encountered in the environment. Recent evidence shows that memories can be permanently altered by manipulating a process called 'reconsolidation.' This process is initiated under certain circumstances, causing a retrieved memory to become destabilised. During the 'reconsolidation window' - the interval between destabilisation and restabilisation - the memory is rendered malleable. These findings suggest an exciting opportunity for treating alcohol problems by weakening the MMMs at the heart of AUD.
In rodents, MMMs can be destabilised using a reminder of previous learning (e.g. a tone that previously signalled drug availability). Since restabilisation requires activity at certain brain receptors (especially NMDARs), it can be blocked pharmacologically. If this occurs, the animal later behaves as if the memory association had been 'erased' and drug seeking stops. Available NMDA antagonists - like ketamine - could similarly be used to block restabilisation of MMMs in humans. It may also be possible to 'overwrite' MMMs behaviourally, by training adaptive new associations while MMMs are unstable. This type of procedure would also be expected to reduce cue-induced craving and drinking.
While these strategies are promising, there are key issues which must be resolved before MMM-modification can be developed for addiction. These are i) that MMMs only destabilise under certain conditions and ii) we cannot yet measure memory destabilisation directly. The critical first step towards developing MMM-modifying treatments for AUD is therefore to develop methods for reliably destabilising MMMs and metrics for measuring this. The primary factor determining memory destabilisation at retrieval is a mismatch between the outcomes predicted by a memory association (e.g. drinking alcohol) and actual outcome (e.g. the drink is withheld), also called a 'prediction error' (PE).This PE enables memory destabilisation when new information about the availability or effects of alcohol coincides with memory retrieval, allowing the memory to be updated with new information.
This project aims to identify robust procedures for destabilising alcohol-MMMs and measuring this destabilisation. To do this we will examine the effects of i) blocking restabilisation using the NMDAR antagonist, ketamine and ii) overwriting destabilised MMMs so that they no longer promote drinking.
In both studies, we manipulate the mismatch between expected and actual drinking outcomes during retrieval of alcohol-MMMs in harmful drinkers. We predict that unexpected information about alcohol availability or value when recalling alcohol-MMMs will cause their destabilisation. In Study I, we aim to block re-stabilisation with ketamine, weakening the alcohol-MMM's ability to activate alcohol seeking and drinking. In Study II, we will use a behavioural procedure to over-write destabilised alcohol-MMMs by training associations between the alcohol cues and unpleasant outcomes (a very bitter drink and aversive pictures) in the reconsolidation window. This procedure should update the effect of alcohol cues from pro- to anti-consummatory. Both interventions should result in reduced alcohol-seeking and drinking.
If one or both of the procedures are successful, they will have significant potential as clinical treatments for AUD, although wider application to other addictions and psychological disorders is also possible.

The brief period of memory instability during memory reconsolidation represents the first viable approach for directly weakening or overwriting the enduring Maladaptive Motivational Memories (MMMs) that underlie addiction in humans. Pharmacological approaches (e.g. NMDAR blockade) while memories are unstable may prevent restabilisation, thus weakening or erasing MMMs. Behavioural approaches (e.g. presenting new associations) while memories are unstable may update MMMs with adaptive information. These approaches may overcome the major limitations of current addiction treatments, namely the lack of long-term efficacy.

However, memory destabilisation does not occur upon every retrieval, leading to the identification of boundary conditions that determine the fate of retrieved memories. The presence of a prediction error at retrieval and the structure of the reminder are critical in destabilising memories, but are currently hard to measure naturalistically. Therefore, despite clinical potential of modifying MMMs via reconsolidation, it is essential to begin with proof-of-principle investigations in humans and identify robust procedures for causing and measuring memory destabilisation in alcohol or drug-using populations.

Here, we will examine procedures for destabilising maladaptive alcohol memories in harmful drinkers by manipulating prediction errors during retrieval. We will probe destabilisation with the NMDAR antagonist ketamine, and behaviourally using disgust counter-conditioning during the putative 'reconsolidation window'. Effects of these interventions on harmful drinking will be assessed. Psychophysiological, behavioural and subjective measures during retrieval will be used to derive an independent 'neurobehavioural signature' of destabilisation that can be used in future studies for intervention development.

1. People with Alcohol Use Disorder (AUD): These will be the primary beneficiaries, although a successful proof-of-principle demonstration through our research with harmful drinkers would suggest that people with a variety of substance use disorders would also be eventual beneficiaries.
How: In the short term, participants in our research, while considered 'sub-clinical,' may benefit throughout the lifetime of this project through reduced harmful drinking. People with AUD (and other substance use disorders) will benefit through involvement in future clinical trials (in the medium term) and as recipients of empirically supported MMM-modifying treatments (long term). Early intervention with young adult drinkers using such treatments in particular, could curtail the longer-term neurocognitive problems associated with chronic alcohol use, improving health, achievement and productivity throughout the lifespan.

2. Wider society: In addition to negative effects on family and other relationships, AUD has far reaching consequences arising from antisocial behaviour, loss of productivity and health spending.
How: Longer-term benefits to the nation's health and economic performance may include improved long-term recovery rates, resulting in reduced NHS spending, as well as improved productivity from lower rates of alcohol-related work absences. In addition, reduced antisocial behaviour means the policing/judiciary/parole systems will be indirect beneficiaries through the redirecting of resources to non-alcohol-related areas of crime.

3. NHS clinicians: Current treatment options for AUD are resource-intensive, yet have limited efficacy.
How: By employing a treatment that targets fundamental addiction processes, clinicians will be more efficient in their treatment and can expect more durable effects using treatments incorporating MMM-modification.

4. Charities: Various charities, such as Alcohol Concern, provide information, education and help to those with alcohol problems.
How: Advisors could educate and advise those with alcohol problems about MMM-modifying treatments. A greater number of people could be encouraged to seek help in the knowledge that a more effective treatment was available.

5. Business: As part of our studies we will develop a smartphone app which identifies craving 'hotspots' and monitors drinking, employing GPS technology.
How: Commercial collaboration with an app development company will ensure an excellent user interface, which will appeal to clinicians and service users as a tool for tracking drinking behaviour. The app may have clinical and commercial potential within the lifetime of the grant.

6. Pharmaceutical industry: There is considerable scope for pharmaceutical development of compounds that can target specific drug memories at reactivation in a temporally specific way. Compounds that either interfere with the restabilisation phase of reconsolidation or improve the likelihood of destabilisation have significant potential as therapeutic agents.
How: Successful identification of a destabilisation procedure will provide a basis for testing novel and existing compounds in humans. In particular, novel (formulations of) NMDAR antagonists with rapid onset and good levels of safety and tolerability may be initial targets for drug development. To increase destabilisation likelihood for robust memory traces, synaptic-plasticity promoting compounds like histone deacetylase inhibitors may also be assessed using our destabilisation metrics.