Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference

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Abstract
Repeated association of drugs of abuse with context leads to long-lasting behavioral responses that reflect reward-controlled learning and participate in the establishment of addiction. Reactivation of consolidated memories is known to produce a reconsolidation process during which memories undergo a labile state. We investigated whether reexposure to drugs had similar effects. Cocaine administration activates extracellular signal-regulated kinase (ERK) in the striatum, and ERK activation is required for the acquisition of cocaine-induced conditioned place preference (CPP). When mice previously conditioned for cocaine-place preference were reexposed to cocaine in the drug-paired compartment after systemic administration of SL327, an inhibitor of ERK activation, CPP response was abolished 24 h later. This procedure also abolished the phosphorylation of ERK and glutamate receptor-1 observed in the ventral and dorsal striatum, 24 h later, during CPP test. Erasure of CPP by SL327 required the combination of cocaine administration and drug-paired context and did not result from enhanced extinction. Similarly, reexposure to morphine in the presence of SL327 long-lastingly abolished response of previously learned morphine-CPP. The effects of SL327 on cocaine- or morphine-CPP were reproduced by protein synthesis inhibition. In contrast, protein synthesis inhibition did not alter previously acquired locomotor sensitization to cocaine. Our findings show that an established CPP can be disrupted when reactivation associates both the conditioned context and drug administration. This process involves ERK, and systemic treatment preventing ERK activation during reexposure erases the previously learned behavioral response. These results suggest potential therapeutic strategies to explore in the context of addiction.