Cocaine-but not methamphetamine-associated memory requires de novo protein synthesis

Abstract

Context-induced drug craving and continuous drug use manifest the critical roles of specific memory episodes associated with the drug use experiences. Drug-induced conditioned place preference (CPP) in C57BL/6J mouse model, in this regard, is an appropriate behavioral paradigm to study such drug use-associated memories. Requirement of protein synthesis in various forms of long-term memory formation and storage has been phylogenetically demonstrated. This study was undertaken to study the requirement of protein synthesis in the learning and memory aspect of the conditioned place preference induced by cocaine and methamphetamine, two abused drugs of choice in local area. Since pCREB has been documented as a candidate substrate for mediating the drug-induced neuroadaptation, the pCREB level in hippocampus, nucleus accumbens, and prefrontal cortex was examined for its potential participation in the formation of CPP caused by these psychostimulants. We found that cocaine (2.5 and 5.0 mg/kg/dose)-induced CPP was abolished by the pretreatment of anisomycin (50 mg/kg/dose), a protein synthesis inhibitor, whereas methamphetamine (0.5 or 1.0 mg/kg/dose)-induced CPP was not affected by the anisomycin pretreatment. Likewise, cocaine-induced CPP was mitigated by another protein synthesis inhibitor, cycloheximide (15 mg/kg/injection) pretreatment, whereas methamphetamine-induced CPP remained intact by such pretreatment. Moreover, anisomycin treatment 2 h after each drug-place pairing disrupted the cocaine-induced CPP, whereas the same treatment did not affect methamphetamine-induced CPP. An increase of accumbal pCREB level was found to associate with the learning phase of cocaine, but not with the learning phase of methamphetamine. We further found that intraaccumbal CREB antisense oligodeoxynucleotide infusion diminished cocaine-induced CPP, whereas did not affect the methamphetamine-induced CPP. Taken together, these data suggest that protein synthesis and accumbal CREB phosphorylation are essential for the learning and consolidation of the cocaine-induced CPP, whereas methamphetamine-induced CPP may be unrelated to the synthesis of new proteins.