Dopamine activates MAPK via PKA/Rap1 in medium spiny neurons (MSNs) expressing the dopamine D1 receptor (D1R)in the nucleus accumbens (NAc), thereby regulating reward-related behavior. However, howMAPKregulates reward-relatedlearning and memory through gene expression is poorly understood. Here, to identify the relevant transcriptional factors, we performed proteomic analysis using affinity beads coated with CREB-binding protein (CBP), a transcriptional coactivator involved in reward-related behavior. We identified more than 100 CBP-interacting proteins, including Neuronal Per-Arnt-Sim domain protein 4 (Npas4). We also found that MAPK phosphorylated Npas4 downstream of PKA, increasing Npas4–CBP interaction and the transcriptional activity of Npas4 at the brain-derived neurotrophic factor (BDNF) promoter. Deletion of Npas4 in the D1R-expressing MSNs impaired cocaine-induced place preference, which was rescued by Npas4-WT but not by a phospho-deficient Npas4 mutant. These observations suggest that MAPK phosphorylates Npas4 in D1R-MSNs and increases its transcriptional activity to enhance reward-related learning and memory.