Advertisement

Cell and Tissue Research

, Volume 375, Issue 1, pp 123–132 | Cite as

Brain neuropeptide S: via GPCR activation to a powerful neuromodulator of socio-emotional behaviors

  • Thomas Grund
  • Inga D. NeumannEmail author
Review

Abstract

Neuropeptide S (NPS) has attracted the attention of the scientific community due to its potent anxiolytic-like and fear-attenuating effects studied in rodents. Therefore, NPS might represent a treatment option for neuropsychiatric disorders, such as anxiety disorders, even more so as single nucleotide polymorphisms in the human NPS receptor gene have been associated with increased anxiety traits that contribute to the pathogenesis of fear- and anxiety-related disorders. However, the signaling mechanisms underlying the behavioral effects of NPS and the interaction with other brain neuropeptides are still rather unknown. To illuminate how NPS modulates the expression of selected emotional and social behaviors, the present review focuses on neuroanatomical and electrophysiological studies, as well as intracellular signaling mechanisms following NPS receptor stimulation in rodents. We will also discuss interactions of the NPS system with two well-described neuropeptides, namely corticotropin-releasing factor and oxytocin, which may contribute to the fear- and anxiety-reducing effects.

Keywords

Neuropeptide S Intracellular signaling Anxiety Fear Neuromodulator 

Notes

Funding information

This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft), German Ministry of Education and Research (Bundesministerium für Bildung und Forschung), EU (FemNatCD) and Bayerische Forschungsstiftung to I.D.N.

References

  1. Adori C, Barde S, Bogdanovic N, Uhlen M, Reinscheid RR, Kovacs GG, Hokfelt T (2015a) Neuropeptide S- and neuropeptide S receptor-expressing neuron populations in the human pons. Front Neuroanat 9:126CrossRefGoogle Scholar
  2. Adori C, Barde S, Vas S, Ebner K, Su J, Svensson C, Mathe AA, Singewald N, Reinscheid RR, Uhlen M, Kultima K, Bagdy G, Hokfelt T (2015b) Exploring the role of neuropeptide S in the regulation of arousal: a functional anatomical study. Brain Struct FunctGoogle Scholar
  3. Allen IC, Pace AJ, Jania LA, Ledford JG, Latour AM, Snouwaert JN, Bernier V, Stocco R, Therien AG, Koller BH (2006) Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease. Am J Physiology Lung Cell Mol Physiol 291:L1005–L1017CrossRefGoogle Scholar
  4. Beiderbeck DI, Lukas M, Neumann ID (2014) Anti-aggressive effects of neuropeptide S independent of anxiolysis in male rats. Front Behav Neurosci 8:185CrossRefGoogle Scholar
  5. 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 281:24704–24712CrossRefGoogle Scholar
  6. Blume A, Bosch OJ, Miklos S, Torner L, Wales L, Waldherr M, Neumann ID (2008) Oxytocin reduces anxiety via ERK1/2 activation: local effect within the rat hypothalamic paraventricular nucleus. Eur J Neurosci 27:1947–1956CrossRefGoogle Scholar
  7. Camarda V, Rizzi A, Ruzza C, Zucchini S, Marzola G, Marzola E, Guerrini R, Salvadori S, Reinscheid RK, Regoli D, Calo G (2009) In vitro and in vivo pharmacological characterization of the neuropeptide s receptor antagonist [D-Cys(tBu)5]neuropeptide S. J Pharmacol Exp Ther 328:549–555CrossRefGoogle Scholar
  8. Chauveau F, Lange MD, Jüngling K, Lesting J, Seidenbecher T, Pape HC (2012) Prevention of stress-impaired fear extinction through neuropeptide s action in the lateral amygdala. Neuropsychopharmacology 37:1588–1599CrossRefGoogle Scholar
  9. Civelli O, Saito Y, Wang Z, Nothacker HP, Reinscheid RK (2006) Orphan GPCRs and their ligands. Pharmacol Ther 110:525–532CrossRefGoogle Scholar
  10. Clark SD, Duangdao DM, Schulz S, Zhang L, Liu X, Xu YL, Reinscheid RK (2011) Anatomical characterization of the neuropeptide S system in the mouse brain by in situ hybridization and immunohistochemistry. J Comp Neurol 519:1867–1893CrossRefGoogle Scholar
  11. Clark SD, Kenakin TP, Gertz S, Hassler C, Gay EA, Langston TL, Reinscheid RK, Runyon SP (2017) Identification of the first biased NPS receptor agonist that retains anxiolytic and memory promoting effects with reduced levels of locomotor stimulation. Neuropharmacology 118:69–78CrossRefGoogle Scholar
  12. Dannlowski U, Kugel H, Franke F, Stuhrmann A, Hohoff C, Zwanzger P, Lenzen T, Grotegerd D, Suslow T, Arolt V, Heindel W, Domschke K (2011) Neuropeptide-S (NPS) receptor genotype modulates basolateral amygdala responsiveness to aversive stimuli. Neuropsychopharmacology 36:1879–1885CrossRefGoogle Scholar
  13. Dimitrov EL, Yanagawa Y, Usdin TB (2013) Forebrain GABAergic projections to locus coeruleus in mouse. J Comp Neurol 521:2373–2397CrossRefGoogle Scholar
  14. Dine J, Ionescu IA, Stepan J, Yen YC, Holsboer F, Landgraf R, Eder M, Schmidt U (2013) Identification of a role for the ventral hippocampus in neuropeptide S-elicited anxiolysis. PLoS One 8:e60219CrossRefGoogle Scholar
  15. Dine J, Ionescu IA, Avrabos C, Yen YC, Holsboer F, Landgraf R, Schmidt U, Eder M (2015) Intranasally applied neuropeptide S shifts a high-anxiety electrophysiological endophenotype in the ventral hippocampus towards a “normal”-anxiety one. PLoS One 10:e0120272CrossRefGoogle Scholar
  16. Domschke K et al (2011) Neuropeptide S receptor gene -- converging evidence for a role in panic disorder. Mol Psychiatry 16:938–948CrossRefGoogle Scholar
  17. Donner J et al (2010) Assessment of the neuropeptide S system in anxiety disorders. Biol Psychiatry 68:474–483CrossRefGoogle Scholar
  18. Duangdao DM, Clark SD, Okamura N, Reinscheid RK (2009) Behavioral phenotyping of neuropeptide S receptor knockout mice. Behav Brain Res 205:1–9CrossRefGoogle Scholar
  19. Ebner K, Rjabokon A, Pape HC, Singewald N (2011) Increased in vivo release of neuropeptide S in the amygdala of freely moving rats after local depolarisation and emotional stress. Amino Acids 41:991–996CrossRefGoogle Scholar
  20. Erdmann F, Kugler S, Blaesse P, Lange MD, Skryabin BV, Pape HC, Jüngling K (2015) Neuronal expression of the human neuropeptide S receptor NPSR1 identifies NPS-induced calcium signaling pathways. PLoS One 10:e0117319CrossRefGoogle Scholar
  21. Fendt M, Imobersteg S, Burki H, McAllister KH, Sailer AW (2010) Intra-amygdala injections of neuropeptide S block fear-potentiated startle. Neurosci Lett 474:154–157CrossRefGoogle Scholar
  22. Grund T, Neumann ID (2018) Neuropeptide S induces acute anxiolysis by phospholipase C-dependent signaling within the medial amygdala. Neuropsychopharmacology 43:1156–1163CrossRefGoogle Scholar
  23. Grund T, Goyon S, Li Y, Eliava M, Liu H, Charlet A, Grinevich V, Neumann ID (2017) Neuropeptide S activates paraventricular oxytocin neurons to induce anxiolysis. J Neurosci 37:12214–12225CrossRefGoogle Scholar
  24. Hasnie FS, Breuer J, Parker S, Wallace V, Blackbeard J, Lever I, Kinchington PR, Dickenson AH, Pheby T, Rice ASC (2007) Further characterization of a rat model of varicella zoster virus-associated pain: relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs. Neuroscience 144:1495–1508CrossRefGoogle Scholar
  25. Ionescu IA, Dine J, Yen YC, Buell DR, Herrmann L, Holsboer F, Eder M, Landgraf R, Schmidt U (2012) Intranasally administered neuropeptide S (NPS) exerts anxiolytic effects following internalization into NPS receptor-expressing neurons. Neuropsychopharmacology 37:1323–1337CrossRefGoogle Scholar
  26. Jüngling K, Blaesse P, Goedecke L, Pape HC (2016) Dynorphin-dependent reduction of excitability and attenuation of inhibitory afferents of NPS neurons in the pericoerulear region of mice. Front Cell Neurosci 10:61CrossRefGoogle Scholar
  27. Jüngling K, Liu X, Lesting J, Coulon P, Sosulina L, Reinscheid RK, Pape HC (2012) Activation of neuropeptide S-expressing neurons in the locus coeruleus by corticotropin-releasing factor. J Physiol 590:3701–3717CrossRefGoogle Scholar
  28. Jüngling K, Lange MD, Szkudlarek HJ, Lesting J, Erdmann FS, Doengi M, Kugler S, Pape HC (2015) Increased GABAergic efficacy of central amygdala projections to neuropeptide S neurons in the brainstem during fear memory retrieval. Neuropsychopharmacology 40:2753–2763CrossRefGoogle Scholar
  29. Jüngling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu YL, Reinscheid RK, Pape HC (2008) Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala. Neuron 59:298–310CrossRefGoogle Scholar
  30. Jurek B, Neumann ID (2018) The oxytocin receptor: from intracellular signaling to behavior. Physiol Rev 98:1805–1908CrossRefGoogle Scholar
  31. Justice NJ, Yuan ZF, Sawchenko PE, Vale W (2008) Type 1 corticotropin-releasing factor receptor expression reported in BAC transgenic mice: implications for reconciling ligand-receptor mismatch in the central corticotropin-releasing factor system. J Comp Neurol 511:479–496CrossRefGoogle Scholar
  32. Klauke B, Deckert J, Zwanzger P, Baumann C, Arolt V, Pauli P, Reif A, Domschke K (2014) Neuropeptide S receptor gene (NPSR) and life events: G x E effects on anxiety sensitivity and its subdimensions. World J Biol Psychiatry 15:17–25CrossRefGoogle Scholar
  33. Knowles JA et al (1998) Results of a genome-wide genetic screen for panic disorder. Am J Med Genet 81:139–147CrossRefGoogle Scholar
  34. Kroenke K, Krebs EE, Bair MJ (2009) Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry 31:206–219CrossRefGoogle Scholar
  35. Laitinen T et al (2004) Characterization of a common susceptibility locus for asthma-related traits. Science 304:300–304CrossRefGoogle Scholar
  36. Leonard SK, Dwyer JM, Sukoff Rizzo SJ, Platt B, Logue SF, Neal SJ, Malberg JE, Beyer CE, Schechter LE, Rosenzweig-Lipson S, Ring RH (2008) Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders. Psychopharmacology 197:601–611CrossRefGoogle Scholar
  37. Li W, Chang M, Peng YL, Gao YH, Zhang JN, Han RW, Wang R (2009) Neuropeptide S produces antinociceptive effects at the supraspinal level in mice. Regul Peptides 156:90–95CrossRefGoogle Scholar
  38. Liao Y, Lu B, Ma Q, Wu G, Lai X, Zang J, Shi Y, Liu D, Han F, Zhou N (2016) Human neuropeptide S receptor is activated via a Galphaq protein-biased signaling cascade by a human neuropeptide S analog lacking the C-terminal 10 residues. J Biol Chem 291:7505–7516CrossRefGoogle Scholar
  39. Liu X, Zeng J, Zhou A, Theodorsson E, Fahrenkrug J, Reinscheid RK (2011) Molecular fingerprint of neuropeptide S-producing neurons in the mouse brain. J Comp Neurol 519:1847–1866CrossRefGoogle Scholar
  40. Liu X, Si W, Garau C, Jungling K, Pape HC, Schulz S, Reinscheid RK (2017) Neuropeptide S precursor knockout mice display memory and arousal deficits. Eur J Neurosci 46:1689–1700CrossRefGoogle Scholar
  41. Logue MW, Vieland VJ, Goedken RJ, Crowe RR (2003) Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromosome 7. Am J Med Genet B Neuropsychiatr Genet 121B:95–99CrossRefGoogle Scholar
  42. Lukas M, Neumann ID (2012) Nasal application of neuropeptide S reduces anxiety and prolongs memory in rats: social versus non-social effects. Neuropharmacology 62:398–405CrossRefGoogle Scholar
  43. Mathew SJ, Price RB, Charney DS (2008) Recent advances in the neurobiology of anxiety disorders: implications for novel therapeutics. Am J Med Genet C Semin Med Genet 148C:89–98CrossRefGoogle Scholar
  44. Meis S, Stork O, Munsch T (2011) Neuropeptide S-mediated facilitation of synaptic transmission enforces subthreshold theta oscillations within the lateral amygdala. PLoS One 6:e18020CrossRefGoogle Scholar
  45. Meis S, Bergado-Acosta JR, Yanagawa Y, Obata K, Stork O, Munsch T (2008) Identification of a neuropeptide S responsive circuitry shaping amygdala activity via the endopiriform nucleus. PLoS One 3:e2695CrossRefGoogle Scholar
  46. Neumann ID, Landgraf R (2012) Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 35:649–659CrossRefGoogle Scholar
  47. Newcomer KL, Shelerud RA, Douglas KSV, Larson DR, Crawford BJ (2010) Anxiety levels, fear-avoidance beliefs, and disability levels at baseline and at 1 year among subjects with acute and chronic low back pain. PM&R 2:514–520CrossRefGoogle Scholar
  48. Okamura N, Habay SA, Zeng J, Chamberlin AR, Reinscheid RK (2008) Synthesis and pharmacological in vitro and in vivo profile of 3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68), a selective antagonist of the neuropeptide S receptor. J Pharm Exp Ther 325:893–901CrossRefGoogle Scholar
  49. Okamura N, Hashimoto K, Iyo M, Shimizu E, Dempfle A, Friedel S, Reinscheid RK (2007) Gender-specific association of a functional coding polymorphism in the neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 31:1444–1448CrossRefGoogle Scholar
  50. Okamura N, Garau C, Duangdao DM, Clark SD, Jüngling K, Pape HC, Reinscheid RK (2011) Neuropeptide S enhances memory during the consolidation phase and interacts with noradrenergic systems in the brain. Neuropsychopharmacology 36:744–752CrossRefGoogle Scholar
  51. Paneda C, Huitron-Resendiz S, Frago LM, Chowen JA, Picetti R, de Lecea L, Roberts AJ (2009) Neuropeptide S reinstates cocaine-seeking behavior and increases locomotor activity through corticotropin-releasing factor receptor 1 in mice. J Neurosci 29:4155–4161CrossRefGoogle Scholar
  52. Pape HC, Jüngling K, Seidenbecher T, Lesting J, Reinscheid RK (2010) Neuropeptide S: a transmitter system in the brain regulating fear and anxiety. Neuropharmacology 58:29–34CrossRefGoogle Scholar
  53. Pausch MH (1997) G-protein-coupled receptors in Saccharomyces cerevisiae: high-throughput screening assays for drug discovery. Trends Biotechnol 15:487–494CrossRefGoogle Scholar
  54. Peng YL, Zhang JN, Chang M, Li W, Han RW, Wang R (2010) Effects of central neuropeptide S in the mouse formalin test. Peptides 31:1878–1883CrossRefGoogle Scholar
  55. Pulga A, Ruzza C, Rizzi A, Guerrini R, Calo G (2012) Anxiolytic- and panicolytic-like effects of neuropeptide S in the mouse elevated T-maze. Eur J Neurosci 36:3531–3537CrossRefGoogle Scholar
  56. Raczka KA, Gartmann N, Mechias ML, Reif A, Buchel C, Deckert J, Kalisch R (2010) A neuropeptide S receptor variant associated with overinterpretation of fear reactions: a potential neurogenetic basis for catastrophizing. Mol Psychiatry 15(1045):1067–1074CrossRefGoogle Scholar
  57. Reinscheid RK (2007) Phylogenetic appearance of neuropeptide S precursor proteins in tetrapods. Peptides 28:830–837CrossRefGoogle Scholar
  58. Reinscheid RK, Xu YL (2005a) Neuropeptide S as a novel arousal promoting peptide transmitter. The FEBS J 272:5689–5693CrossRefGoogle Scholar
  59. Reinscheid RK, Xu YL (2005b) Neuropeptide S and its receptor: a newly deorphanized G protein-coupled receptor system. Neuroscientist 11:532–538CrossRefGoogle Scholar
  60. Reinscheid RK, Xu YL, Okamura N, Zeng J, Chung S, Pai R, Wang Z, Civelli O (2005) Pharmacological characterization of human and murine neuropeptide s receptor variants. J Pharmacol Exp Ther 315:1338–1345CrossRefGoogle Scholar
  61. Reme SE, Tangen T, Moe T, Eriksen HR (2011) Prevalence of psychiatric disorders in sick listed chronic low back pain patients. Eur J Pain 15:1075–1080CrossRefGoogle Scholar
  62. Reyes BA, Drolet G, Van Bockstaele EJ (2008) Dynorphin and stress-related peptides in rat locus coeruleus: contribution of amygdalar efferents. J Comp Neurol 508:663–675CrossRefGoogle Scholar
  63. Reyes BA, Valentino RJ, Xu G, Van Bockstaele EJ (2005) Hypothalamic projections to locus coeruleus neurons in rat brain. Eur J Neurosci 22:93–106CrossRefGoogle Scholar
  64. Rizzi A, Vergura R, Marzola G, Ruzza C, Guerrini R, Salvadori S, Regoli D, Calo G (2008) Neuropeptide S is a stimulatory anxiolytic agent: a behavioural study in mice. Br J Pharmacol 154:471–479CrossRefGoogle Scholar
  65. Roozendaal B, McEwen BS, Chattarji S (2009) Stress, memory and the amygdala. Nat Rev Neurosci 10:423–433CrossRefGoogle Scholar
  66. Ruzza C, Asth L, Guerrini R, Trapella C, Gavioli EC (2015) Neuropeptide S reduces mouse aggressiveness in the resident/intruder test through selective activation of the neuropeptide S receptor. Neuropharmacology 97:1–6CrossRefGoogle Scholar
  67. Ruzza C, Pulga A, Rizzi A, Marzola G, Guerrini R, Calo G (2012) Behavioural phenotypic characterization of CD-1 mice lacking the neuropeptide S receptor. Neuropharmacology 62:1999–2009CrossRefGoogle Scholar
  68. Ruzza C, Rizzi A, Trapella C, Pela M, Camarda V, Ruggieri V, Filaferro M, Cifani C, Reinscheid RK, Vitale G, Ciccocioppo R, Salvadori S, Guerrini R, Calo G (2010) Further studies on the pharmacological profile of the neuropeptide S receptor antagonist SHA 68. Peptides 31:915–925CrossRefGoogle Scholar
  69. Sartori SB, Maurer V, Murphy C, Schmuckermair C, Muigg P, Neumann ID, Whittle N, Singewald N (2016) Combined neuropeptide S and D-cycloserine augmentation prevents the return of fear in extinction-impaired rodents: advantage of dual versus single drug approaches. Int J Neuropsychopharmacol 19Google Scholar
  70. Sato S, Shintani Y, Miyajima N, Yoshimura K (2002) Novel G protein-coupled receptor protein and DNA thereof. In: World Patent ApplicationGoogle Scholar
  71. Shimomura Y, Harada M, Goto M, Sugo T, Matsumoto Y, Abe M, Watanabe T, Asami T, Kitada C, Mori M, Onda H, Fujino M (2002) Identification of neuropeptide W as the endogenous ligand for orphan G-protein-coupled receptors GPR7 and GPR8. J Biol Chem 277:35826–35832CrossRefGoogle Scholar
  72. Slattery DA, Naik RR, Grund T, Yen YC, Sartori SB, Fuchsl A, Finger BC, Elfving B, Nordemann U, Guerrini R, Calo G, Wegener G, Mathe AA, Singewald N, Czibere L, Landgraf R, Neumann ID (2015) Selective breeding for high anxiety introduces a synonymous SNP that increases neuropeptide s receptor activity. J Neurosci 35:4599–4613CrossRefGoogle Scholar
  73. Swanson LW, Sawchenko PE (1983) Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 6:269–324CrossRefGoogle Scholar
  74. Tang XL, Wang Y, Li DL, Luo J, Liu MY (2012) Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets. Acta Pharmacol Sin 33:363–371CrossRefGoogle Scholar
  75. Toth I, Neumann ID, Slattery DA (2012) Social fear conditioning: a novel and specific animal model to study social anxiety disorder. Neuropsychopharmacology 37:1433–1443CrossRefGoogle Scholar
  76. van den Burg EH, Stindl J, Grund T, Neumann ID, Strauss O (2015) Oxytocin stimulates extracellular Ca(2+) influx through TRPV2 channels in hypothalamic neurons to exert its anxiolytic effects. Neuropsychopharmacology 40:2938–2947CrossRefGoogle Scholar
  77. Vitale G, Filaferro M, Ruggieri V, Pennella S, Frigeri C, Rizzi A, Guerrini R, Calo G (2008) Anxiolytic-like effect of neuropeptide S in the rat defensive burying. Peptides 29:2286–2291CrossRefGoogle Scholar
  78. Wegener G, Finger BC, Elfving B, Keller K, Liebenberg N, Fischer CW, Singewald N, Slattery DA, Neumann ID, Mathe AA (2011) Neuropeptide S alters anxiety, but not depression-like behaviour in Flinders sensitive line rats: a genetic animal model of depression. Int J Neuropsychopharmacol:1–13Google Scholar
  79. 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 500:84–102CrossRefGoogle Scholar
  80. 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 43:487–497CrossRefGoogle Scholar
  81. Zhang S, Jin X, You Z, Wang S, Lim G, Yang J, McCabe M, Li N, Marota J, Chen L, Mao J (2014) Persistent nociception induces anxiety-like behavior in rodents:role of endogenous neuropeptide S. PainGoogle Scholar
  82. Zoicas I, Menon R, Neumann ID (2016) Neuropeptide S reduces fear and avoidance of con-specifics induced by social fear conditioning and social defeat, respectively. Neuropharmacology 108:284–291CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Behavioural and Molecular Neurobiology, Regensburg Center of NeuroscienceUniversity of RegensburgRegensburgGermany

Personalised recommendations