AbstractCorticotropin releasing factor (CRF) has been implicated to act as a neurotransmitter or modulator in central nervous activation during stress. In this study, we examined the regulatory effect ofCRFon the expression and function of the norepinephrine transporter (NET)in vitro.SK‐N‐BE(2) M17 cells were exposed to different concentrations ofCRFfor different periods. Results showed that exposure of cells toCRFsignificantly increasedmRNAand protein levels ofNETin a concentration‐ and time‐dependent manner. TheCRF‐induced increase inNETexpression was mimicked by agonists of eitherCRFreceptor 1 or 2. Furthermore, similarCRFtreatments induced a parallel increase in the uptake of [3H] norepinephrine. Both increased expression and function ofNETcaused byCRFwere abolished by simultaneous administration ofCRFreceptor antagonists, indicating a mediation byCRFreceptors. However, there was no additive effect for the combination of both receptor antagonists. Chromatin immunoprecipitation assays confirm an increased acetylation of histone H3 on theNETpromoter following treatment withCRF. Taken together, this study demonstrates thatCRFup‐regulates the expression and function ofNETin vitro. This regulation is mediated throughCRFreceptors and an epigenetic mechanism related to histone acetylation may be involved. ThisCRF‐induced regulation onNETexpression and function may play a role in development of stress‐related depression and anxiety.imageThis study demonstrated that corticotropin release factor (CRF) up‐regulated the expression and function of norepinephrine transporter (NET) in a concentration‐ and time‐dependent manner, through activation of CRF receptors and possible histone acetylation in NET promoter. The results indicate that their interaction may play an important role in stress‐related physiological and pathological status.