Learned associations between the rewarding effect of addictive drugs and drug-paired contexts resist extinction and contribute to the high rate of relapse observed in drug addicts.Although it has been shown that extracellular signal-regulated kinase 1/2(ERK1/2) activity in the nucleus accumbens(NAc) is modulated by the primary rewarding effect of opiates,little is known as to its role in the morphine-associated contextual memory.In the present study,we investigated the ERK1/2 activity indicated by phosphorylated ERK1/2(pERK1/2) levels in rats using a morphine-induced conditioned place preference(CPP) procedure.Our results showed that,in rats that had undergone morphine conditioning,after testing(expression phase) pERK1/2 in the NAc shell but not the NAc core or the adjacent caudate putamen was specifically increased.pERK1/2 levels in several other parts of the brain involved in drug-seeking,such as the medial prefrontal cortex,dorsal hippocampus,and basolateral amygdala,showed no significant changes.A significant positive correlation was observed between the elevated pERK1/2 level in the NAc shell and the degree of conditioned preference for morphine-associated contexts.Bilateral injection of an inhibitor of ERK activation into the NAc shell attenuated ERK1/2 phosphorylation and the expression of morphine CPP,but injections into the core did not.Selective inhibition of NR2B-containing NMDA receptor in the NAc shell by ifenprodil prevented CPP expression and down-regulated local ERK1/2 phosphorylation.These findings collectively suggest that recall of morphine-associated contextual memory depends specifically upon ERK1/2 activation in the NAc shell and that ERK1/2 phosphorylation is regulated by the upstream NR2B-containing NMDA receptor. Learned associations between the rewarding effect of addictive drugs and drug-paired contexts resist extinction and contribute to the high rate of relapse in drug addicts. Though it has been shown that extracellular signal-regulated kinase 1/2 (ERK1 / 2) activity in the nucleus accumbens (NAc) is modulated by the primary rewarding effect of opiates, little is known as to its role in the morphine-associated contextual memory. In the present study, we investigated the ERK1 / 2 activity indicated by phosphorylated ERK1 / 2 ( pERK1 / 2) levels in rats using a morphine-induced conditioned place preference (CPP) procedure. Our results showed that, in rats that had undergone morphine conditioning, after testing (expression phase) pERK1 / 2 in the NAc shell but not the NAc core or the adjacent caudate putamen was increased. pERK1 / 2 levels in several other parts of the brain involved in drug-seeking, such as the medial prefrontal cortex, dorsal hippocampus, and basolateral amygdala, showed no signi ficant changes. A significant positive correlation was observed between the elevated pERK1 / 2 level in the NAc shell and the degree of conditioned preference for morphine-associated contexts.Bilateral injection of an inhibitor of ERK activation into the NAc shell attenuated ERK1 / 2 phosphorylation and the expression of morphine CPP, but injections into the core did not. Selective inhibition of NR2B-containing NMDA receptor in the NAc shell by ifenprodil prevented CPP expression and down-regulated local ERK1 / 2 phosphorylation.These findings collectively recall that morphine- associated contextual memory depends specifically upon ERK1 / 2 activation in the NAc shell and that ERK1 / 2 phosphorylation is regulated by the upstream NR2B-containing NMDA receptor.