Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders

Abstract

Rationale

Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently deorphaned G protein-coupled receptor system. Recent reports implicate NPS in the mediation of anxiolytic-like activity in rodents.

Objectives

To extend the characterization of NPS, the present studies examined the in vitro pharmacology of mouse NPSR and the in vivo pharmacology of NPS in three preclinical mouse models predictive of anxiolytic action: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). The ability of NPS to produce antidepressant-like effects in the tail suspension test (TST) was also investigated.

Results

In vitro, mouse NPS_1–20 (mNPS_1–20) and the C-terminal glutamine-truncated mouse NPS_1–19 bound mNPSR with high affinity (K _i  = 0.203 ± 0.060, 0.635 ± 0.141 nM, respectively) and potently activated intracellular calcium release (EC₅₀ = 3.73 ± 1.08, 4.10 ± 1.25 nM). NPS produced effects in vivo consistent with anxiolytic-like activity. In FPT, NPS increased punished crossings (minimal effective dose [MED]: mNPS_1–20 = 0.2 μg, mNPS_1–19 = 0.02 μg), similar to the reference anxiolytic, alprazolam (MED 0.5 μg). NPS increased the percentage of time spent in the open quadrants of EZM (MED: mNPS_1–20 = 0.1 μg, mNPS_1–19 = 1.0 μg), like the reference anxiolytic, chlordiazepoxide (MED 56 μg). In SIH, NPS attenuated stress-induced increases in body temperature similar to alprazolam but with a large potency difference between the NPS peptides (MED: mNPS_1–20 = 2.0 μg, mNPS_1–19 = 0.0002 μg) and mNPS_1–20 increased baseline temperature. Unlike fluoxetine, NPS did not effect immobility time in TST, indicating a lack of antidepressant-like activity.

Conclusions

These data provide an important confirmation and expansion of the anxiolytic-like effects of NPS and implicate the NPS system as a novel target for anxiolytic drug discovery.