Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders
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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.
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.
In vitro, mouse NPS1–20 (mNPS1–20) and the C-terminal glutamine-truncated mouse NPS1–19 bound mNPSR with high affinity (Ki = 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]: mNPS1–20 = 0.2 μg, mNPS1–19 = 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: mNPS1–20 = 0.1 μg, mNPS1–19 = 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: mNPS1–20 = 2.0 μg, mNPS1–19 = 0.0002 μg) and mNPS1–20 increased baseline temperature. Unlike fluoxetine, NPS did not effect immobility time in TST, indicating a lack of antidepressant-like activity.
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.
KeywordsGPR154 PGR14 GPRA Vasopressin-related receptor (VRR1) Depression Oxytocin
- Bernier V, Stocco R, Bogusky MJ, Joyce JG, Parachoniak C, Grenier K, Arget M, Mathieu MC, O’Neill GP, Slipetz D, Crackower MA, Tan CM, Therien AG (2006) Structure–function relationships in the neuropeptide S receptor: molecular consequences of the asthma-associated mutation N107I. J Biol Chem 281:24704–24712PubMedCrossRefGoogle Scholar
- Mori M, Hayashi K, Miya H, Sato S, Kitada C, Matsumoto H, Nagi T, Shimomura T (2002) Novel polypeptide, DNA thereof and use of the same. European Patent EP1433849Google Scholar
- Roth AL, Marzola E, Rizzi A, Arduin M, Trapella C, Corti C, Vergura R, Martinelli P, Salvadori S, Regoli D, Corsi M, Cavanni P, Calo G, Guerrini R (2006) Structure-activity studies on neuropeptide S: identification of the amino acid residues crucial for receptor activation. J Biol Chem 281:20809–20816PubMedCrossRefGoogle Scholar
- Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:1 (page following 696)PubMedCrossRefGoogle Scholar