Investigating the effect of Arvcf reveals an essential role on regulating the mesolimbic dopamine signaling-mediated nicotine reward.

The mesolimbic dopamine system is crucial for drug reinforcement and reward learning, leading to addiction. We previously demonstrated that Arvcf was associated significantly with nicotine and alcohol addiction through genome-wide association studies. However, the role and mechanisms of Arvcf in dopamine-mediated drug reward processes were largely unknown. In this study, we first showed that Arvcf mediates nicotine-induced reward behavior by using conditioned place preference (CPP) model on Arvcf-knockout (Arvcf-KO) animal model. Then, we revealed that Arvcf was mainly expressed in VTA dopaminergic neurons whose expression could be upregulated by nicotine treatment. Subsequently, our SnRNA-seq analysis revealed that Arvcf was directly involved in dopamine biosynthesis in VTA dopaminergic neurons. Furthermore, we found that Arvcf-KO led to a significant reduction in both the dopamine synthesis and release in the nucleus accumbens (NAc) on nicotine stimulation. Specifically, we demonstrated that inhibition of Arvcf in VTA dopaminergic neurons decreased dopamine release within VTA-NAc circuit and suppressed nicotine reward-related behavior, while overexpression of Arvcf led to the opposite results. Taken together, these findings highlight the role of Arvcf in regulating dopamine signaling and reward learning, and its enhancement of dopamine release in the VTA-NAc circuit as a novel mechanism for nicotine reward.