Psychopharmacology

, Volume 197, Issue 4, pp 601–611

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

  • Sarah K. Leonard
  • Jason M. Dwyer
  • Stacey J. Sukoff Rizzo
  • Brian Platt
  • Sheree F. Logue
  • Sarah J. Neal
  • Jessica E. Malberg
  • Chad E. Beyer
  • Lee E. Schechter
  • Sharon Rosenzweig-Lipson
  • Robert H. Ring
Original Investigation

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 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.

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.

Keywords

GPR154 PGR14 GPRA Vasopressin-related receptor (VRR1) Depression Oxytocin 

References

  1. Aron C, Simon P, Larousse C, Boissier JR (1971) Evaluation of a rapid technique for detecting minor tranquilizers. Neuropharmacology 10:459–469PubMedCrossRefGoogle Scholar
  2. Beck B, Fernette B, Stricker-Krongrad A (2005) Peptide S is a novel potent inhibitor of voluntary and fast-induced food intake in rats. Biochem Biophys Res Commun 332:859–865PubMedCrossRefGoogle Scholar
  3. 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
  4. Borsini F, Lecci A, Volterra G, Meli A (1989) A model to measure anticipatory anxiety in mice? Psychopharmacology (Berl) 98:207–211CrossRefGoogle Scholar
  5. Boules M, Shaw A, Fredrickson P, Richelson E (2007) Neurotensin agonists: potential in the treatment of schizophrenia. CNS Drugs 21:13–23PubMedCrossRefGoogle Scholar
  6. Bourin M, Hascoet M, Mansouri B, Colombel MC, Bradwejn J (1992) Comparison of behavioral effects after single and repeated administrations of four benzodiazepines in three mice behavioral models. J Psychiatry Neurosci 17:72–77PubMedGoogle Scholar
  7. Bouwknecht JA, Olivier B, Paylor RE (2007) The stress-induced hyperthermia paradigm as a physiological animal model for anxiety: a review of pharmacological and genetic studies in the mouse. Neurosci Biobehav Rev 31:41–59CrossRefGoogle Scholar
  8. Bystritsky A (2006) Treatment-resistant anxiety disorders. Mol Psychiatry 11:805–814PubMedCrossRefGoogle Scholar
  9. Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108PubMedCrossRefGoogle Scholar
  10. Chiou LC, Liao YY, Fan PC, Kuo PH, Wang CH, Riemer C, Prinssen EP (2007) Nociceptin/orphanin FQ peptide receptors: pharmacology and clinical implications. Curr Drug Targets 8:117–135PubMedCrossRefGoogle Scholar
  11. Cryan JF, Mombereau C, Vassout A (2005) The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29:571–625PubMedCrossRefGoogle Scholar
  12. Gupte J, Cutler G, Chen JL, Tian H (2004) Elucidation of signaling properties of vasopressin receptor-related receptor 1 by using the chimeric receptor approach. Proc Natl Acad Sci USA 101:1508–1513PubMedCrossRefGoogle Scholar
  13. Hascoet M, Bourin M, Colombel MC, Fiocco AJ, Baker GB (2000) Anxiolytic-like effects of antidepressants after acute administration in a four-plate test in mice. Pharmacol Biochem Behav 65:339–344PubMedCrossRefGoogle Scholar
  14. Hunkeler W, Mohler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290:514–516PubMedCrossRefGoogle Scholar
  15. Kash SF, Tecott LH, Hodge C, Baekkeskov S (1999) Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 96:1698–1703PubMedCrossRefGoogle Scholar
  16. Kinkead B, Nemeroff CB (2006) Novel treatments of schizophrenia: targeting the neurotensin system. CNS Neurol Disord Drug Targets 5:205–218PubMedGoogle Scholar
  17. Koob GF, Greenwell TN (2004) Neuropeptide S: a novel activating anxiolytic? Neuron 43:441–442PubMedCrossRefGoogle Scholar
  18. Malberg JE, Platt B, Rizzo SJ, Ring RH, Lucki I, Schechter LE, Rosenzweig-Lipson S (2007) Increasing the levels of insulin-like growth factor-i by an igf binding protein inhibitor produces anxiolytic and antidepressant-like effects. Neuropsychopharmacology 32:2360–2368PubMedCrossRefGoogle Scholar
  19. 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
  20. Nielsen DM (2006) Corticotropin-releasing factor type-1 receptor antagonists: the next class of antidepressants? Life Sci 78:909–919PubMedCrossRefGoogle Scholar
  21. Olivier B, Zethof T, Pattij T, van Boogaert M, van Oorschot R, Leahy C, Oosting R, Bouwknecht A, Veening J, van der Gugten J, Groenink L (2003) Stress-induced hyperthermia and anxiety: pharmacological validation. Eur J Pharmacol 463:117–132PubMedCrossRefGoogle Scholar
  22. Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–67PubMedCrossRefGoogle Scholar
  23. Porsolt RD, Deniel M, Jalfre M (1979) Forced swimming in rats: hypothermia, immobility and the effects of imipramine. Eur J Pharmacol 57:431–436PubMedCrossRefGoogle Scholar
  24. Pulkkinen V, Majuri ML, Wang G, Holopainen P, Obase Y, Vendelin J, Wolff H, Rytila P, Laitinen LA, Haahtela T, Laitinen T, Alenius H, Kere J, Rehn M (2006) Neuropeptide S and G protein-coupled receptor 154 modulate macrophage immune responses. Hum Mol Genet 15:1667–1679PubMedCrossRefGoogle Scholar
  25. Rajarao SJ, Platt B, Sukoff SJ, Lin Q, Bender CN, Nieuwenhuijsen BW, Ring RH, Schechter LE, Rosenzweig-Lipson S, Beyer CE (2007) Anxiolytic-like activity of the non-selective galanin receptor agonist, galnon. Neuropeptides 41:307–320PubMedCrossRefGoogle Scholar
  26. Reinscheid RK (2007) Phylogenetic appearance of neuropeptide S precursor proteins in tetrapods. Peptides 28:830–837PubMedCrossRefGoogle Scholar
  27. Ring RH (2005) The central vasopressinergic system: examining the opportunities for psychiatric drug development. Curr Pharm Des 11:205–225PubMedCrossRefGoogle Scholar
  28. Ring RH, Malberg JE, Potestio L, Ping J, Boikess S, Luo B, Schechter LE, Rizzo S, Rahman Z, Rosenzweig-Lipson S (2006) Anxiolytic-like activity of oxytocin in male mice: behavioral and autonomic evidence, therapeutic implications. Psychopharmacology (Berl) 185:218–225CrossRefGoogle Scholar
  29. 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
  30. 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
  31. Shepherd JK, Grewal SS, Fletcher A, Bill DJ, Dourish CT (1994) Behavioural and pharmacological characterisation of the elevated “zero-maze” as an animal model of anxiety. Psychopharmacology (Berl) 116:56–64CrossRefGoogle Scholar
  32. Shimazaki T, Yoshimizu T, Chaki S (2006) Melanin-concentrating hormone MCH1 receptor antagonists: a potential new approach to the treatment of depression and anxiety disorders. CNS Drugs 20:801–811PubMedCrossRefGoogle Scholar
  33. Smith KL, Patterson M, Dhillo WS, Patel SR, Semjonous NM, Gardiner JV, Ghatei MA, Bloom SR (2006) Neuropeptide S stimulates the hypothalamo–pituitary–adrenal axis and inhibits food intake. Endocrinology 147:3510–3518PubMedCrossRefGoogle Scholar
  34. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 85:367–370CrossRefGoogle Scholar
  35. Valdez GR (2006) Development of CRF1 receptor antagonists as antidepressants and anxiolytics: progress to date. CNS Drugs 20:887–896PubMedCrossRefGoogle Scholar
  36. Varty GB, Cohen-Williams ME, Hunter JC (2003) The antidepressant-like effects of neurokinin NK1 receptor antagonists in a gerbil tail suspension test. Behav Pharmacol 14:87–95PubMedGoogle Scholar
  37. Vendelin J, Pulkkinen V, Rehn M, Pirskanen A, Raisanen-Sokolowski A, Laitinen A, Laitinen LA, Kere J, Laitinen T (2005) Characterization of GPRA, a novel G protein-coupled receptor related to asthma. Am J Respir Cell Mol Biol 33:262–270PubMedCrossRefGoogle Scholar
  38. Xu YL, Reinscheid RK, Huitron-Resendiz S, Clark SD, Wang Z, Lin SH, Brucher FA, Zeng J, Ly NK, Henriksen SJ, de Lecea L, Civelli O (2004) Neuropeptide S: a neuropeptide promoting arousal and anxiolytic-like effects. Neuron 43:487–497PubMedCrossRefGoogle Scholar
  39. Xu YL, Gall CM, Jackson VR, Civelli O, Reinscheid RK (2007) Distribution of neuropeptide S receptor mRNA and neurochemical characteristics of neuropeptide S-expressing neurons in the rat brain. J Comp Neurol 500:84–102PubMedCrossRefGoogle Scholar
  40. Zhang Y, Kowal D, Kramer A, Dunlop J (2003) Evaluation of FLIPR Calcium 3 Assay Kit—a new no-wash fluorescence calcium indicator reagent. J Biomol Screen 8:571–577PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Sarah K. Leonard
    • 1
  • Jason M. Dwyer
    • 1
  • Stacey J. Sukoff Rizzo
    • 1
  • Brian Platt
    • 1
  • Sheree F. Logue
    • 1
  • Sarah J. Neal
    • 1
  • Jessica E. Malberg
    • 1
  • Chad E. Beyer
    • 1
  • Lee E. Schechter
    • 1
  • Sharon Rosenzweig-Lipson
    • 1
  • Robert H. Ring
    • 1
  1. 1.Depression and Anxiety Disorders, Discovery NeuroscienceWyeth ResearchPrincetonUSA

Personalised recommendations