Therefore, NPS might represent a treatment option for neuropsychiatric disorders, such as anxiety disorders, even more so as single nucleotide polymorphisms in the human NPS receptor gene have been associated with increased anxiety traits that contribute to the pathogenesis of fear- and anxiety-related disorders.
Neuropeptide S (NPS), an endogenous neuropeptide that improves short term memory, activates arousal and decreases anxiety is likely to counteract the SR-induced impairment of STM.
Given the behavioral actions of this peptide and the wide innervation pattern, we examined the cellular effects of NPS within two brain stem nuclei known to play a critical role in anxiety and arousal: the dorsal raphe (DR) and laterodorsal tegmentum (LDT).
In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.<b>SIGNIFICANCE STATEMENT</b> Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor.
Overall, phenotypical changes in NPS<sup>-/-</sup> mice are similar to those observed in NPS receptor knockout mice and support earlier findings that suggest major functions of the NPS system in arousal, regulation of anxiety and stress, and memory formation.
Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety.
Since central administration of neuropeptide S (NPS) has been shown to exert anxiolytic effects on rodent behavior in a number of studies, genetic variants of its cognate G-protein coupled receptor (NPSR1) became the focus of several recent human studies on anxiety and anxiety disorders.
These findings further corroborate a major role of the neuropeptide S system in the pathogenesis of anxiety and suggest a potentially beneficial use of therapeutic agents targeting the NPS system in anxiety disorders.
These results not only enlighten the path of NPS in the brain, but also establish a non-invasive method for NPS administration in mice, thus strongly encouraging translation into a novel therapeutic approach for pathological anxiety in humans.
In summary, the present findings - extending previous evidence from rodent studies - for the first time provide support for a complex, non-linear interaction of the neuropeptide S and adenosinergic systems affecting the affect-modulated startle response as an intermediate phenotype of anxiety in humans.
CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS.
The G protein-coupled receptor neuropeptide S receptor 1 (NPSR1) and its ligand neuropeptide S (NPS) form a signaling system mainly implicated in susceptibility to asthma and inflammatory disorders in humans and regulation of anxiety and arousal in rodents.