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


OBJECTIVE
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 (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]: mNPS 1-20 = 0.2 microg, mNPS(1-19) = 0.02 microg), similar to the reference anxiolytic, alprazolam (MED 0.5 microg). NPS increased the percentage of time spent in the open quadrants of EZM (MED: mNPS 1-20 = 0.1 microg, mNPS 1-19 = 1.0 microg), like the reference anxiolytic, chlordiazepoxide (MED 56 microg). 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 microg, mNPS 1-19 = 0.0002 microg) 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.
Leonard
Sarah K
SK
Depression and Anxiety Disorders, Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543, USA. leonars2@wyeth.com
Dwyer
Jason M
JM
Sukoff Rizzo
Stacey J
SJ
Platt
Brian
B
Logue
Sheree F
SF
Neal
Sarah J
SJ
Malberg
Jessica E
JE
Beyer
Chad E
CE
Schechter
Lee E
LE
Rosenzweig-Lipson
Sharon
S
Ring
Robert H
RH
D000525:Alprazolam / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000523:psychology*; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000523:psychology; D001143:Arousal / Q000187:drug effects; D001833:Body Temperature Regulation / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002707:Chlordiazepoxide / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005239:Fear / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000494:pharmacology* / Q000627:therapeutic use*; D010121:Oxytocin; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000502:physiology; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; C484532:NPSR1 protein, human; C515062:NPSR1 protein, mouse; D009479:Neuropeptides; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C506531:neuropeptide S, human; C483314:vasopressin receptor-related receptor 1, human; D005473:Fluoxetine; D010121:Oxytocin; D002707:Chlordiazepoxide; D002118:Calcium; D000525:Alprazolam