Skip to main content
SpringerLink
Log in

Neuropeptide S differently modulates alcohol-related behaviors in alcohol-preferring and non-preferring rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Neuropeptide S (NPS) displays unique pharmacological properties and induces both anxiolytic and pro-stress/arousal activities. Previous studies performed using Wistar rats demonstrated that NPS facilitated alcohol and cocaine seeking but did not affect alcohol or cocaine consumption.

Objectives

Here, we investigated the effects of NPS in Marchigian Sardinian alcohol-preferring (msP) rats, a rat strain characterized by excessive alcohol consumption comorbid with heightened anxiety and depressive-like phenotypes. Specifically, we evaluated the effect of NPS on operant alcohol self-administration by msP rats compared to Wistar rats. The effect of NPS on cue-induced reinstatement of alcohol seeking in msP rats was also evaluated. Finally, using the open field test (OFT) and the elevated plus maze (EPM), we evaluated the effects of NPS on locomotor activity and anxiety.

Results

NPS reduced alcohol self-administration but did not affect cue-induced reinstatement in the msP rat. In addition, NPS induced reinstatement of extinguished alcohol seeking in Wistar rats without affecting alcohol intake. In the EPM task, NPS, in accordance with its anxiolytic activity, increased the time spent in the open arm of the arena by msP rats, although this effect was not observed in Wistar rats.

Conclusions

These data suggest that the effect of NPS is strongly influenced by the genetic background of the animal. In Wistar rats, NPS acts as a pro-arousal agent to promote the reinstatement of alcohol seeking. However, when alcohol drinking is motivated by or associated with a state of pathological anxiety, NPS attenuates alcohol consumption and seeking due to its anxiolytic activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Ayanwuyi LO, Carvajal F, Lerma-Cabrera JM, Domi E, Bjork K, Ubaldi M, Heilig M, Roberto M, Ciccocioppo R, Cippitelli A (2013) Role of a genetic polymorphism in the corticotropin-releasing factor receptor 1 gene in alcohol drinking and seeking behaviors of Marchigian Sardinian alcohol-preferring rats. Front Psychiatry 4:23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Badia-Elder NE, Henderson AN, Bertholomey ML, Dodge NC, Stewart RB (2008) The effects of neuropeptide S on ethanol drinking and other related behaviors in alcohol-preferring and -nonpreferring rats. Alcohol Clin Exp Res 32:1380–1387

    Article  CAS  PubMed  Google Scholar 

  • Cannella N, Economidou D, Kallupi M, Stopponi S, Heilig M, Massi M, Ciccocioppo R (2009) Persistent increase of alcohol-seeking evoked by neuropeptide S: an effect mediated by the hypothalamic hypocretin system. Neuropsychopharmacology 34:2125–34

    Article  CAS  PubMed  Google Scholar 

  • Cannella N, Kallupi M, Ruggeri B, Ciccocioppo R, Ubaldi M (2012) The role of the neuropeptide S system in addiction: Focus on its interaction with the CRF and hypocretin/orexin neurotransmission. Prog Neurobiol 100:48–59

  • Cannella N, Kallupi M, Ruggeri B, Ciccocioppo R, Ubaldi M (2013) The role of the neuropeptide S system in addiction: focus on its interaction with the CRF and hypocretin/orexin neurotransmission. Prog Neurobiol 100:48–59

    Article  CAS  PubMed  Google Scholar 

  • Ciccocioppo R (2013) Genetically selected alcohol preferring rats to model human alcoholism. Curr Top Behav Neurosci 13:251–69

    Article  PubMed  Google Scholar 

  • Ciccocioppo R, de Guglielmo G, Hansson AC, Ubaldi M, Kallupi M, Cruz MT, Oleata CS, Heilig M, Roberto M (2014) Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors. J Neurosci 34:363–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciccocioppo R, Economidou D, Cippitelli A, Cucculelli M, Ubaldi M, Soverchia L, Lourdusamy A, Massi M (2006) Genetically selected Marchigian Sardinian alcohol-preferring (msP) rats: an animal model to study the neurobiology of alcoholism. Addict Biol 11:339–55

    Article  PubMed  PubMed Central  Google Scholar 

  • Ciccocioppo R, Panocka I, Froldi R, Colombo G, Gessa GL, Massi M (1999) Antidepressant-like effect of ethanol revealed in the forced swimming test in Sardinian alcohol-preferring rats. Psychopharmacology (Berl) 144:151–7

    Article  CAS  Google Scholar 

  • Cippitelli A, Ayanwuyi LO, Barbier E, Domi E, Lerma-Cabrera JM, Carvajal F, Scuppa G, Li H, Ubaldi M, Heilig M, Roberto M, Ciccocioppo R (2015) Polymorphism in the corticotropin-releasing factor receptor 1 (CRF1-R) gene plays a role in shaping the high anxious phenotype of Marchigian Sardinian alcohol-preferring (msP) rats. Psychopharmacology (Berl) 232:1083–93

    Article  CAS  Google Scholar 

  • de Guglielmo G, Martin-Fardon R, Teshima K, Ciccocioppo R, Weiss F (2015) MT-7716, a potent NOP receptor agonist, preferentially reduces ethanol seeking and reinforcement in post-dependent rats. Addict Biol 20:643–51

    Article  PubMed  Google Scholar 

  • Gehlert DR, Cippitelli A, Thorsell A, Le AD, Hipskind PA, Hamdouchi C, Lu J, Hembre EJ, Cramer J, Song M, McKinzie D, Morin M, Ciccocioppo R, Heilig M (2007) 3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethyl- imidazo[1,2-b]pyridazine: a novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism. J Neurosci 27:2718–26

    Article  CAS  PubMed  Google Scholar 

  • Ghazal P, Ciccocioppo R, Ubaldi M (2013) Morphine dependence is associated with changes in neuropeptide S receptor expression and function in rat brain. Peptides 46:6–12

    Article  CAS  PubMed  Google Scholar 

  • Gozzi A, Agosta F, Massi M, Ciccocioppo R, Bifone A (2013) Reduced limbic metabolism and fronto-cortical volume in rats vulnerable to alcohol addiction. Neuroimage 69:112–9

    Article  CAS  PubMed  Google Scholar 

  • Hansson AC, Cippitelli A, Sommer WH, Ciccocioppo R, Heilig M (2007) Region-specific down-regulation of Crhr1 gene expression in alcohol-preferring msP rats following ad lib access to alcohol. Addict Biol 12:30–4

    Article  CAS  PubMed  Google Scholar 

  • Hansson AC, Cippitelli A, Sommer WH, Fedeli A, Bjork K, Soverchia L, Terasmaa A, Massi M, Heilig M, Ciccocioppo R (2006) Variation at the rat Crhr1 locus and sensitivity to relapse into alcohol seeking induced by environmental stress. Proc Natl Acad Sci U S A 103:15236–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jungling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu Y-L, Reinscheid RK, Pape H-C (2008) Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala. Neuron 59:298–310

    Article  PubMed  PubMed Central  Google Scholar 

  • Kallupi M, Cannella N, Economidou D, Ubaldi M, Ruggeri B, Weiss F, Massi M, Marugan J, Heilig M, Bonnavion P, de Lecea L, Ciccocioppo R (2010) Neuropeptide S facilitates cue-induced relapse to cocaine seeking through activation of the hypothalamic hypocretin system. Proc Natl Acad Sci U S A 107:19567–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kallupi M, de Guglielmo G, Cannella N, Li HW, Calo G, Guerrini R, Ubaldi M, Renger JJ, Uebele VN, Ciccocioppo R (2013) Hypothalamic Neuropeptide S receptor blockade decreases discriminative cue-induced reinstatement of cocaine seeking in the rat. Psychopharmacology (Berl) 226:347–55

    Article  CAS  Google Scholar 

  • Laas K, Reif A, Akkermann K, Kiive E, Domschke K, Lesch KP, Veidebaum T, Harro J (2015) Neuropeptide S receptor gene variant and environment: contribution to alcohol use disorders and alcohol consumption. Addict Biol 20:605–16

    Article  CAS  PubMed  Google Scholar 

  • 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 (Berl) 197:601–611

    Article  CAS  Google Scholar 

  • Leonard SK, Ring RH (2011) Immunohistochemical localization of the neuropeptide S receptor in the rat central nervous system. Neuroscience 172:153–63

    Article  CAS  PubMed  Google Scholar 

  • 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 519:1847–66

    Article  CAS  PubMed  Google Scholar 

  • Lukas M, Neumann ID (2012) Nasal application of neuropeptide S reduces anxiety and prolongs memory in rats: social versus non-social effects. Neuropharmacology 62:398–405

    Article  CAS  PubMed  Google Scholar 

  • 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(7):e2695

    Article  PubMed  PubMed Central  Google Scholar 

  • Okamura N, Reinscheid RK (2007) Neuropeptide S: a novel modulator of stress and arousal. Stress 10:221–6

    Article  CAS  PubMed  Google Scholar 

  • 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 29:4155–4161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pape HC, Jungling K, Seidenbecher T, Lesting J, Reinscheid RK (2010) Neuropeptide S: a transmitter system in the brain regulating fear and anxiety. Neuropharmacology 58:29–34

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1988) The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press, San Diego

    Google Scholar 

  • Reinscheid RK (2007) Phylogenetic appearance of neuropeptide S precursor proteins in tetrapods. Peptides 28:830–7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reinscheid RK (2008) Neuropeptide S: anatomy, pharmacology, genetics and physiological functions. Results Probl Cell Differ 46:145–58

    Article  CAS  PubMed  Google Scholar 

  • 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 154:471–479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schank JR, Ryabinin AE, Giardino WJ, Ciccocioppo R, Heilig M (2012) Stress-related neuropeptides and addictive behaviors: beyond the usual suspects. Neuron 76:192–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart RB, Gatto GJ, Lumeng L, Li TK, Murphy JM (1993) Comparison of alcohol-preferring (P) and nonpreferring (NP) rats on tests of anxiety and for the anxiolytic effects of ethanol. Alcohol 10:1–10

    Article  CAS  PubMed  Google Scholar 

  • Ubaldi M, Giordano A, Severi I, Li H, Kallupi M, de Guglielmo G, Ruggeri B, Stopponi S, Ciccocioppo R, Cannella N (2016) Activation of hypocretin-1/orexin-A neurons projecting to the bed nucleus of the stria terminalis and paraventricular nucleus is critical for reinstatement of alcohol seeking by neuropeptide S. Biol Psychiatry 79:452–62

    Article  CAS  PubMed  Google Scholar 

  • 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 29:2286–2291

    Article  CAS  PubMed  Google Scholar 

  • Weiss F, Mitchiner M, Bloom FE, Koob GF (1990) Free-choice responding for ethanol versus water in alcohol preferring (P) and unselected Wistar rats is differentially modified by naloxone, bromocriptine, and methysergide. Psychopharmacology (Berl) 101:178–86

  • Xu Y-L, 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 500:84–8102

    Article  CAS  PubMed  Google Scholar 

  • Xu Y-L, 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 43:487–497

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Rina Righi and Mariangela Fiorelli for animal care and Alfredo Fiorelli for technical support. This work was supported by National Institutes of Health grants RO1 AA017447 and RO1 AA014351 from the National Institute on Alcohol Abuse and Alcoholism.

Author information

Authors and Affiliations

  1. School of Pharmacy, Pharmacology Unit, University of Camerino, Building of Experimental Medicine, Via Madonna delle Carceri 9, Camerino, MC, 62032, Italy

    Nazzareno Cannella, Marsida Kallupi, Hong Wu Li, Serena Stopponi, Carlo Cifani, Roberto Ciccocioppo & Massimo Ubaldi

Authors
  1. Nazzareno Cannella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marsida Kallupi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hong Wu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Serena Stopponi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carlo Cifani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roberto Ciccocioppo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Massimo Ubaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massimo Ubaldi.

Ethics declarations

All procedures adhered to the European Community Council Directive and the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and were approved by the Ethics Committee of the University of Camerino (Protocol no. 1/2012).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cannella, N., Kallupi, M., Li, H.W. et al. Neuropeptide S differently modulates alcohol-related behaviors in alcohol-preferring and non-preferring rats. Psychopharmacology 233, 2915–2924 (2016). https://doi.org/10.1007/s00213-016-4333-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-016-4333-7

Keywords

Search

Navigation