Inactivation of PKMζ in the NAc shell abolished cocaine-conditioned reward.

Preventing relapse to drug use is a major challenge for the treatment of drug addiction. Environmental cues are among the major determinants of relapse in abstinent cocaine users. The protein kinase M ζ (PKMζ) is involved in the generation and maintenance of long-term potentiation and is critical in memory storage. Here we show that inhibition of PKMζ in the nucleus accumbens (NAc) shell, a major component of the reward system that plays an important role in mediating drug craving and relapse, by a selective inhibitor ζ inhibitory peptide (ZIP), abolished cocaine-induced conditioned place preference (CPP). However, the injection of ZIP into the NAc core resulted in earlier onset of CPP extinction. Finally, we found that the levels of PKMζ and GluR2 in the NAc remained unchanged, while the GluR1 levels were elevated following CPP and fully reversed by ZIP injection. Together, our results suggest that inactivation of PKMζ in the NAc may result in the dissociation between the rewarding properties of the drug and the drug-related environment and may serve as a novel target for the treatment of drug relapse.