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

摘要

Relapse to alcohol abuse is often caused by exposure to potent alcohol-associated cues. Therefore, disruption of the cue-alcohol memory can prevent relapse. It is believed that memories destabilize and become prone for updating upon their reactivation through retrieval and then restabilize within 6 h during a "reconsolidation" process. We recently showed that relapse to cocaine seeking in a place-conditioning paradigm could be prevented by counterconditioning the cocaine cues with aversive outcomes following cocaine-memory retrieval. However, to better model addiction-related behaviors, self-administration models are necessary. Here, we demonstrate that relapse to alcohol seeking can be prevented by aversive counterconditioning conducted during alcohol-memory reconsolidation, in the place conditioning and operant self-administration paradigms, in mice and rats, respectively. We found that the reinstatement of alcohol-conditioned place preference was abolished only when aversive counterconditioning with water flooding was given shortly after alcohol-memory retrieval. Furthermore, rats trained to lever press for alcohol showed decreased context-induced renewal of alcohol-seeking responding when the lever pressing was punished with foot-shocks, shortly, but not 6 h, after memory retrieval. These results suggest that aversive counterconditioning can prevent relapse to alcohol seeking only when performed during alcohol-memory reconsolidation, presumably by updating, or replacing, the alcohol memory with aversive information. Finally, we found that aversive counterconditioning preceded by alcohol-memory retrieval was characterized by the upregulation of brain-derived neurotrophic factor (Bdnf) mRNA expression in the medial prefrontal cortex, suggesting that BDNF may play a role in the memory updating process.