On the Resistance to Relapse to Cocaine-Seeking Following Impairment of Instrumental Cocaine Memory Reconsolidation

Abstract

Reconsolidation normally functions to update and maintain memories in the long-term. However, this process can be disrupted pharmacologically to weaken memories. Exploiting such experimental amnesia to disrupt the maladaptive reward memories underpinning addiction may provide a novel therapeutic avenue to prevent relapse. Here, we tested whether targeted disruption of the reconsolidation of instrumental (operant) lever pressing for cocaine resulted in protection against different forms of relapse in a rat self-administration model. We first confirmed that systemic injection of the non-competitive N-methyl–D-aspartate receptor (NMDAR) antagonist MK-801 did impair reconsolidation to reduce spontaneous instrumental drug-seeking memory at test. This deficit was not rescued by pharmacological induction of stress with the anxiogenic α2-noradrenergic receptor antagonist yohimbine. In contrast, cocaine-seeking was restored to control levels following priming with cocaine itself, or presentation of a cocaine-associated cue. These results suggest that while stress-induced relapse can be reduced by disruption of instrumental memory reconsolidation, the apparent sparing of the pavlovian cue-drug memory permitted other routes to relapse. Therefore, future reconsolidation-based therapeutic strategies for addictive drug-seeking may need to target both instrumental and pavlovian memories.

Postretrieval Microinjection of Baclofen Into the Agranular Insular Cortex Inhibits Morphine-Induced CPP by Disrupting Reconsolidation

“…Reconsolidation is usually characterized as a process that allows memory strength to be adjusted or updated by integrating new information into the original memory during a limited period after reactivation or retrieval, and it has aroused great interest in disruption of the maladaptive memories of drug addiction (Exton-McGuinness et al, 2019;Rich et al, 2020). Our study observed the effects of intra-AI BLF on the reconsolidation of CPP in mice via behavioral pharmacology methods.…”

“…The cause of the repeated recovery of extinction may be that it does not erase or modify the original CS-US associative memory to the greatest extent (Dunsmoor et al, 2015). In contrast, previously maladaptive reward memories underpinning addiction can be disrupted or erased pharmacologically following retrieval of the memory trace (Exton-McGuinness et al, 2019). Therefore, reconsolidation-based therapeutic strategies for addictive drug-seeking and preventing relapse maybe more promising than enhancing the consolidation of extinction learning.…”

Disruption of relapse to alcohol seeking by aversive counterconditioning following memory retrieval

“…Thus, operant self‐administration procedures are used as a better model to study a variety of aspects in addiction, 22,36 including alcohol relapse after prolonged voluntary consumption 21,38 . Targeting the memories underlying operant behaviors via reconsolidation mechanisms has been particularly challenging, 41,42 yet feasible 13–15,42 . Thus, attenuation of operant responding can be achieved via pharmacological interference with memory reconsolidation, 12,13,42 yet only a few studies tested behavioral manipulations, such as retrieval‐extinction 14,15,18 .…”

Targeting the Reconsolidation of Licit Drug Memories to Prevent Relapse: Focus on Alcohol and Nicotine

“…The authors concluded that operant (instrumental) memories [ 30 ] are more resistant to this manipulation following retrieval, compared with the Pavlovian memories targeted in their previous study [ 28 ]. Indeed, targeting the memories underlying operant behaviors via reconsolidation mechanisms has been particularly challenging [ 37 , 38 ], yet feasible with a thorough selection and adjustment of memory retrieval procedures [ 25 , 38 , 39 , 40 , 41 ].…”