Dual‐specificity phosphatase 15 (DUSP15) in the nucleus accumbens is a novel negative regulator of morphine‐associated contextual memory
Xiaomeng Qiao, Yongsheng Zhu, Wei Dang, Runzhi Wang, Mizhu Sun, Yuanyuan Chen, Yuhui Shi, Lirong Zhang
Abstract
Drug relapse among addicts often occurs due to the learned association between drug-paired cues and the rewarding effects of these drugs, such as morphine. Contextual memory associated with morphine has a central role in maintenance and relapse. We showed that morphine-conditioned place preference (CPP) activates extracellular-regulated protein kinase (ERK) in the nucleus accumbens (NAc). The main enzymes that mediate ERK dephosphorylation are members of the dual-specificity phosphatase (DUSP) superfamily. It is unclear which members regulate the morphine CPP-induced activation of ERK. After screening, DUSP15 was found to be decreased during both morphine CPP expression and the reinstatement period. Intra-NAc infusions of AAV-DUSP15 (overexpression) not only prevented the expression of morphine-induced CPP but also facilitated extinction, inhibited reinstatement, and abolished ERK activation. However, after repeated morphine exposure and withdrawal in mice, there was no change in the expression of p-ERK and DUSP15, and the overexpression of DUSP15 in the NAc did not improve the impaired spatial memory or anxiety-like behaviour induced by morphine. Together, these findings indicate that DUSP15 not only prevents the expression of drug-paired contextual memory but also promotes the extinction of existing addiction memories, thus providing a novel therapeutic target for the treatment of drug addiction.