Neuropeptide S facilitates extinction of fear via modulation of mesolimbic dopaminergic circuitry

The inability to extinguish learned fear is a hallmark of trauma- and stress-related disorders. A form of inhibitory learning called fear extinction is an effective way to treat these disorders. However, the neurobiology of fear extinction has not been clarified. The involvement of a dopaminergic pathway from the ventral tegmental area (VTA) to the nucleus accumbens shell (AcbSh) in fear extinction has been suggested. Several neuropeptide systems, including neuropeptide S (NPS), modulate the activity of VTA dopaminergic neurons. Herein, we investigated the role of NPS in modulating the VTA-AcbSh circuit in fear extinction. While the NPS-containing neurons of the pericoerulear (periLC) area project to the VTA, the recipient cells are equipped with NPS receptors. Using a Pavlovian fear conditioning procedure, we tested the effect of NPS on fear extinction in male Wistar rats. Intra-VTA administration of NPS prior to fear extinction training facilitated the fear extinction learning and memory, however, NPS receptors antagonist had the opposite effect. Fear extinction training increased the dopamine efflux and cFOS immunoreactivity in the AcbSh area of NPS-treated rats compared with the vehicle-injected controls. We suggest that the NPS neurons of the periLC project to the VTA and might facilitate fear extinction by enhancing the activity of mesolimbic dopaminergic circuit. •NPS containing neurons of periLC project to the VTA.•Dopaminergic neurons of the VTA may co-express NPS receptors.•NPS in the VTA facilitated, while NPS receptors antagonist impaired fear extinction.•Intra-VTA NPS treatment increased dopamine release and cFOS expression in AcbSh.