As a noninvasive behavioral intervention, the retrieval-extinction (R-E) procedure has drawn much research attention for its capacity to target the reconsolidation of maladaptive memories. However, later research findings suggest that the cause and consequence of R-E may be more complicated than previously suggested. For example, the R-E procedure could increase an animal's motivation for drug-seeking under certain circumstances, and the reversed extinction-retrieval (E-R) procedure could also suppress the drug memory. Two possible mechanisms underlying the R-E procedure have been proposed: the reconsolidation-update and extinction-facilitation hypotheses. To elucidate the paradoxical prior findings and examine these two hypotheses, we systematically examined the efficacy of the extinction (E), R-E, and E-R procedures in mice's low-dose versus high-dose cocaine-induced conditioned place preference (CPP) memory. We showed that the dose of cocaine is a crucial determinant of the efficacy of the three behavioral interventions. The E procedure exerted a long-lasting suppression of the low-dose cocaine CPP memory, while the R-E procedure induced more memory defects than the E and E-R procedures in its long-term suppression of the high-dose cocaine CPP memory. It warrants further investigation of whether the R-E procedure's underlying neurochemical and molecular mechanisms differ from the E and E-R procedures.
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