Neuropeptide S: a novel modulator of stress and arousal.

Neuropeptide S (NPS) is a recently identified bioactive peptide that modulates stress and arousal. NPS is expressed in a few discrete nuclei in the brainstem, such as the pericoerulear (locus coeruleus (LC)) area and the parabrachial nucleus. NPS activates its cognate G protein-coupled receptor at low nanomolar agonist concentrations and induces elevation of intracellular Ca2+ and cAMP, therefore acting as an excitatory transmitter. The NPS receptor is widely expressed in the brain, including regions known to regulate stress responses such as hypothalamus, thalamus, amygdala and limbic cortex. We have recently reported that the NPS system can modulate stress responses and induce wakefulness based on a battery of behavioral tests. Activation of NPS receptors induces arousal and reduces all sleep stages. At the same time, NPS produces anxiolytic-like effects in rodents. These studies indicate that the NPS system has a unique pharmacological profile to promote both anxiolytic and arousal effects. NPS might interact with other hypothalamic neuropeptide systems that are known to be involved in stress and appetite control and thus might be a valuable target for development of a new class of drugs to treat anxiety disorders.