Addiction: a drug-induced disorder of memory reconsolidation

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Persistent maladaptive memories that maintain drug seeking and are resistant to extinction are a hallmark of addiction. As such, disruption of memory reconsolidation after retrieval has received attention for its therapeutic potential. Unrestrained reconsolidation may have the opposite effect, leading to reiterative and cumulative strengthening of memory over long periods of time. Here we review the molecular mechanisms underlying reconsolidation of appetitive and drug-rewarded memories, and discuss how these findings contribute to our understanding of the nature of this process. Finally, we suggest that drug-induced alterations to signal transduction might lead to dysregulation of reconsolidation, causing enhancements of drug-related memory after retrieval, and significantly contribute to the compulsive drug seeking that is a core component of addiction.

Highlights

► Reconsolidation functions to maintain or update memories after retrieval. ► Reconsolidation may primarily mediate emotional or motivational aspects of memory. ► Mechanisms of reconsolidation significantly overlap with those of consolidation. ► Drug exposure alters signal transduction and may enhance reconsolidation. ► Dysregulated reconsolidation may thereby contribute to the etiology of addiction.

Section snippets

How is reconsolidation studied?

The protocol for studying memory reconsolidation typically involves three phases: a training phase, a reactivation phase after which manipulations occur, and test (see Figure 1A). Memory reactivation is triggered by presentation of the conditioned stimulus (CS), without (and sometimes with) the occurrence of the unconditioned stimulus (US).

In general, study of memory requires a change in behavior. For example, we attribute expression of a response to a previously reinforced cue to the formation

Molecular mechanisms of reconsolidation

In the studies discussed here, reward-related Pavlovian tasks, including conditioned place preference and Pavlovian approached are used, with drug, food, or sucrose reinforcers. By detailing the similarities with other processes and specificity of activation in time, task, and brain region after retrieval, a picture of the mechanisms of reconsolidation in these paradigms has started to emerge. NMDA receptors play a crucial role in memory reconsolidation [18, 21, 22, 23, 24, 25, 26, 27, 28] as

What is stabilized during reconsolidation?

Evidence for altered behavioral responses after a nonreinforced reactivation trial is commonly interpreted as reflecting changes to the memory. However, it is not clear as to what aspect of the memory is modified. The original formulation of reconsolidation stated that disruptions of reconsolidation were disruptions of the CS-US association or the content of the memory [6]. There is evidence, however, that disruptions of reconsolidation primarily disrupt affective, rather than associative

Role of reconsolidation in addiction

Enhancement of memory after retrieval supports the hypothesis that reconsolidation is a real, specific process that maintains, strengthens, and possibly updates memory. These findings also raise the possibility that dysfunctional reconsolidation processes might also be involved in the etiology of disorders including addiction. For example, repeated drug use and chronic alterations to signal transduction may cause ongoing strengthening of memory. Here, continuing to strengthen memories after

Molecular mechanisms may provide a framework for understanding reconsolidation

Elucidating the molecular mechanisms of reconsolidation is an important step toward understanding the long-term storage and ongoing maintenance of memory. Thus far, our limited understanding of the mechanisms underlying memory reconsolidation has generated some insight into the nature of this process. The apparent similarity of signaling underlying reconsolidation and consolidation suggests that there is also a functional concordance of these mechanisms. That is, reconsolidation is likely

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was funded in part by National Institute of Drug Abuse DA015222 (JRT) and National Institute of Mental Health MH093459 (NCT).

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