Molecular and synaptic mechanisms regulating drug-associated memories: Towards a bidirectional treatment strategy

The successful treatment of substance use disorders is dependent on the establishment of a long-term abstinent state. Relapse can be suppressed by interfering with memories of drug use that are evoked by re-exposure to drug-associated contexts and cues. Two strategies for accomplishing this goal are either to prevent drug-memory reconsolidation or to induce the formation of a competing, extinction memory. However, clinical attempts to prolong abstinence by behavioral modification of drug-related memories have had limited success. One approach to improve behavioral treatment strategies is to identify the molecular mechanisms that regulate these memory processes and then use pharmacological tools as supplements to improve efficacy. Still, due to the involvement of several overlapping signaling cascades in both reconsolidation and extinction, it is difficult to specifically modify one of the two processes. For example, attempting to elicit extinction may instead initiate reconsolidation, resulting in the unintentional strengthening of drug-related memories. A better approach is to identify diverging components of the two processes, whereby a single medication would simultaneously weaken reconsolidation and enhance extinction. This review will provide an overview of the neural substrates that are involved in the regulation of drug-associated memories, and will discuss emerging approaches to pharmacologically weaken these memories, including recent efforts to precisely and bidirectionally target reconsolidation and extinction. Ultimately, pharmacologically-enhanced memory-based approaches have the potential to produce more informed relapse-prevention therapies.