1School of Psychological Sciences and 2Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 69978, Israel.
Relapse to drug abuse is a critical clinical issue, often caused by exposure to drug-associated cues. Thus, disruption of the cue-drug memory can prevent cue-induced craving and relapse. Memories become labile upon their retrieval for a temporary “reconsolidation window”, during which they restabilize. Hence, relapse can be prevented by disruption of drug memory reconsolidation, typically by protein synthesis inhibitors. However, the latter evoke serious side-effects. Therefore, behavioral procedures capable of disrupting memory reconsolidation are crucial. Aversion therapies have been used to prevent cue-induced craving with limited success. In this approach, drug-paired cues are re-associated (via counterconditioning) with aversive outcomes. However, the previous drug-cue memory may recover, triggering relapse to drug seeking. We therefore tested whether aversive counterconditioning applied within the “reconsolidation window” could interfere with the cue-drug memory, and abolish relapse to cocaine seeking. Mice were trained in a conditioned place preference (CPP) procedure. One side of a CPP box was associated with cocaine or alcohol, and was later counterconditioned with the emetic effect of LiCl, or with water aversion. We found that when counterconditioning was applied without a prior memory retrieval, mice relapsed to drug seeking, but conducting counterconditioning shortly after memory retrieval (within the reconsolidation window) prevented relapse. Moreover, mice relapsed when counterconditioned outside the reconsolidation window (before or long-after memory retrieval). Finally, when mice were first conditioned to place aversion, and then counterconditioned with cocaine during reconsolidation, relapse of place aversion was also prevented. Our findings suggest that post-retrieval counterconditioning leads to replacement of the existing cue-drug memory with a cue-aversion memory, and thereby prevents relapse, as the cue ceases to evoke craving. Thus, this novel behavioral paradigm can possibly serve as a safe method to prevent relapse to maladaptive behaviors.