Dual-specificity phosphatase 15 (DUSP15) in the nucleus accumbens is a novel negative regulator of morphine-associated contextual memory.

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.