PKMζ Maintains Drug Reward and Aversion Memory in the Basolateral Amygdala and Extinction Memory in the Infralimbic Cortex

The intense associative memories that develop between drug-paired contextual cues and rewarding stimuli or the drug withdrawal-associated aversive feeling have been suggested to contribute to the high rate of relapse. Various studies have elucidated the mechanisms underlying the formation and expression of drug-related cue memories, but how this mechanism is maintained is unknown. Protein kinase M zeta (PKM zeta) was recently shown to be necessary and sufficient for long-term potentiation maintenance and memory storage. In the present study, we used conditioned place preference (CPP) and aversion (CPA) to examine whether PKM zeta maintains both morphine-associated reward memory and morphine withdrawal-associated aversive memory in the basolateral amygdala (BLA). We also investigate the role of PKM zeta in the infralimbic cortex in the extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues. We found that intra-BLA but not central nucleus of the amygdala injection of the selective PKM zeta inhibitor ZIP 1 day after CPP and CPA training impaired the expression of CPP and CPA 1 day later, and the effect of ZIP on memory lasted at least 2 weeks. Inhibiting PKMz activity in the infralimbic cortex, but not prelimbic cortex, disrupted the expression of the extinction memory of CPP and CPA. These results indicate that PKM zeta in the BLA is required for the maintenance of associative morphine reward memory and morphine withdrawal-associated aversion memory, and PKM zeta in the infralimbic cortex is required for the maintenance of extinction memory of morphine reward-related cues and morphine withdrawal-related aversive cues. Neuropsychopharmacology (2011) 36, 1972-1981; doi: 10.1038/npp. 2011.63; published online 1 June 2011