Skip to main content
SpringerLink
Log in

Evaluation of the anxiolytic-like effect of NKP608, a NK1-receptor antagonist, in two rat strains that differ in anxiety-related behaviors

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

Abstract

Rationale

NKP608, a selective NK1 receptor antagonist, has been shown to produce anxiolytic-like effects in rodents tested in different anxiety models. However, most of these findings are based on social behaviors and, to our knowledge, there is no report concerning the effects of NKP608 in the elevated plus-maze (EPM) and the open field (OF), two classical models of anxiety/emotionality. Moreover, this compound has never been tested in rodent strains that display contrasting levels of anxiety-related behaviors.

Objectives

To investigate the anxiolytic-like effects of NKP608 in Lewis and SHR inbred rats, proposed as a genetic model of anxiety for showing high and low indices of anxiety, respectively.

Methods

Lewis and SHR rats of both sexes were tested in the EPM and OF tests following acute administration of NKP608 (0.003, 0.03 or 0.3 mg/kg) or chlordiazepoxide (CDZ, 5 mg/kg). Measures of approach/avoidance towards the open arms of the EPM and the central area of the OF were used as indices of anxiety.

Results

All doses of NKP608 produced anxiolytic-like effects, similar to those of CDZ, in SHR males tested in the OF but not in the EPM. Conversely, this compound had a partial anxiolytic effect in LEW males (and, to a lower degree, in SHR females) in the EPM, but not in the OF. LEW females were unaffected following all pharmacological treatments.

Conclusions

These findings indicate that the anxiety-related effects of NKP608 are strain-, sex- and test-dependent. Moreover, the present data confirm and extend the therapeutic potential of NK1 receptor antagonists for the treatment of anxiety.

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

Access this article

Log in via an institution

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.

Similar content being viewed by others

References

  • Aguiar MS, Brandão ML (1996) Effects of microinjections of the neuropeptide substance P in the dorsal periaqueductal gray on the behavior of rats in the plus-maze test. Physiol Behav 60:1183–1186

    Article  CAS  PubMed  Google Scholar 

  • Angrini M, Leslie JC, Shephard RA (1998) Effects of propanolol, buspirone, pCPA, reserpine, and chlordiazepoxide on open-field behavior. Pharmacol Biochem Behav 59:387–397

    Article  CAS  PubMed  Google Scholar 

  • Bilkei-Gorzo A, Racz I, Michel K, Zimmer A (2002) Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene. J Neurosci 22:10046–10052

    CAS  PubMed  Google Scholar 

  • Boyce S, Smith D, Carlson E, Hewson L, Rigby M, O`Donnel R, Harrison T, Rupniak NMJ (2001) Intra-amygdala injection of the substance P (NK1 receptor) antagonist L-760735 inhibits neonatal vocalisations in guinea-pigs. Neuropharmacology 41:130–137

    Article  CAS  PubMed  Google Scholar 

  • Cheeta S, Tucci S, Sandhu J, Williams AR, Rupniak NMJ, File SE (2001) Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the social interaction test in gerbils. Brain Res 915:170–175

    Article  CAS  PubMed  Google Scholar 

  • De Lima TC, Ribeiro SJ (1996) Central effects of tachykinin NK receptor agonists and antagonists on the elevated plus-maze behavior in rats. Soc Neurosci Abstr 22:1154

    Google Scholar 

  • File SE (1997) Anxiolytic action of a neurokinin1 receptor antagonist in the social interaction test. Pharmacol Biochem Behav 58:747–752

    Article  CAS  PubMed  Google Scholar 

  • File SE (2000) NKP608, an NK1 receptor antagonist, has an anxiolytic action in the social interaction test in rats. Psychopharmacology 152:105–109

    Article  CAS  PubMed  Google Scholar 

  • Fink G, Sumner BE, Rosie R, Grace O, Quinn JP (1996) Estrogen control of central neurotransmission: effect on mood, mental state, and memory. Cell Mol Neurobiol 16:325–344

    Article  CAS  PubMed  Google Scholar 

  • Fischer CE, Hughes RN (1996) Effects of diazepam and cyclohexyladenosine on open-field behavior in rats perinatally exposed to caffeine. Life Sci 58:701–709

    Article  Google Scholar 

  • Gavioli EC, Canteras NS, De Lima TCM (1999) Anxiogenic-like effect induced by substance P injected into the lateral septal nucleus. Neuroreport 10:3399–3403

    Article  CAS  PubMed  Google Scholar 

  • Gentsch C, Cutler M, Vassout A, Veenstra S, Brugger F (2002) Anxiolytic effect of NKP608, a NK1-receptor antagonist, in the social investigation test in gerbils. Behav Brain Res 133:363–368

    Article  CAS  PubMed  Google Scholar 

  • Godfroid IO (1999) Sex differences relating to psychiatric treatment. Can J Psychiatry 44:362–367

    Article  CAS  PubMed  Google Scholar 

  • Gray JA, Flint J, Dawson GR, Fulker DW (1999) A Strategy to home-in on polygenes influencing susceptibility to anxiety. Hum Psychopharmacol Clin Exp 14:S3–S10

    Article  Google Scholar 

  • Gyertyán I (1992) Animal models of anxiety: a critical review. Acta Physiol Hungarica 79:369–379

    Google Scholar 

  • Hall CS (1934) Emotional behavior in the rat. I., Defecation and urination as measures of individual differences in emotionality. J Comp Psychol 18:385–403

    Article  Google Scholar 

  • Hall CS (1936) Emotional behavior in the rat. III The relationship between emotionality and ambulatory activity. J Comp Psychol 22:345–452

    Article  Google Scholar 

  • Handley SL, McBlane JW (1993) An assessment of the elevated X-maze for studying anxiety and anxiety-modulating drugs. J Pharmacol Toxicol Meth 29:129–138

    Article  CAS  Google Scholar 

  • Hasenöhrl RU, Jentjens O, Silva AS, Tomaz C, Huston JP (1998) Anxiolytic-like action of neurokinin substance P administered systemically or into the nucleus basalis magnocellularis region. Eur J Pharmacol 354:123–133

    Article  PubMed  Google Scholar 

  • Hogg SA (1996) Review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacol Biochem Behav 54:21–30

    Article  CAS  PubMed  Google Scholar 

  • Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Stramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NMJ (1998) Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281:1640–1645

    Article  CAS  PubMed  Google Scholar 

  • Lesch KP (2001) Molecular foundation of anxiety disorders. J Neural Transm 108:717–746

    Article  CAS  PubMed  Google Scholar 

  • Montgomery KC (1955) The relation between fear induced by novel stimulation and exploratory behavior. J Comp Physiol Psychol 48:254–260

    Article  CAS  PubMed  Google Scholar 

  • Otsuka M, Yoshioka K (1993) Neurotransmitter functions of mammalian tachykinins. Physiol Rev 73:229–308

    Article  CAS  PubMed  Google Scholar 

  • Papp M, Vassout A, Gentsch C (2000) The NK1-receptor antagonist NKP608 has an antidepressant-like effect in the chronic mild stress model of depression in rats. Behav Brain Res 115:19–23

    Article  CAS  PubMed  Google Scholar 

  • Pellow S, Chopin P, File SE, Briley M (1985) Validation of open, closed arms entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Meth 14:149–167

    Article  CAS  Google Scholar 

  • Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33

    Article  CAS  PubMed  Google Scholar 

  • Ramos A, Mormède P (1998) Stress and emotionality: a multidimensional and genetic approach. Neurosci Biobehav Rev 22:33–57

    Article  CAS  PubMed  Google Scholar 

  • Ramos A, Berton O, Mormède P, Chaouloff F (1997) A multiple-test study of anxiety-related behaviors in six inbred rat strains. Behav Brain Res 85:57–69

    Article  CAS  PubMed  Google Scholar 

  • Ramos A, Mellerin Y, Mormède P, Chaouloff F (1998) A genetic and multifactorial analysis of anxiety-related behaviours in Lewis and SHR intercrosses. Behav Brain Res 96:195–205

    Article  CAS  PubMed  Google Scholar 

  • Ramos A, Moisan M-P, Chaouloff F, Mormède C, Mormède P (1999) Identification of female-specific QTLs affecting an emotionality-related behavior in rats. Mol Psychiatry 4:453–462

    Article  CAS  PubMed  Google Scholar 

  • Ramos A, Kangerski AL, Basso PF, Da Silva Santos JE, Assreuy J, Vendruscolo LF, Takahashi RN (2002) Evaluation of Lewis and SHR rat strain as a genetic model for the study of anxiety and pain. Behav Brain Res 129:113–123

    Article  PubMed  Google Scholar 

  • Ribeiro-da-Silva A, Hökfelt T (2000) Neuroanatomical localisation of substance P in the CNS and sensory neurons. Neuropeptides 34:256–271

    Article  CAS  PubMed  Google Scholar 

  • Rupniak NMJ, Carlson EC, Harrison T, Oates B, Seward E, Owen S, Felipe C, Hunt S, Wheeldon A (2000) Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalization in guinea-pigs and mice. Neuropharmacology 39:1413–1421

    Article  CAS  PubMed  Google Scholar 

  • Santarelli L, Gobbi G, Debs PC, Sibille EL, Blier P, Hen R, Heath MJS (2001) Genetic and pharmacological disruption of neurokinin1 receptor function decrease anxiety-related behaviors and increases serotonergic function. Proc Natl Acad Sci USA 98:1912–1917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spooren WPJM, Schoeffter P, Gasparini F, Kuhn R, Gentsch C (2002) Pharmacological and endocrinological characterization of stress-induced hyperthermia in single housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608). Eur J Pharmacol 435:161–170

    Article  CAS  PubMed  Google Scholar 

  • Stout SC, Owens MJ, Nemeroff CB (2001) Neurokinin 1 receptor antagonists as potential antidepressants. Annu Rev Pharmacol Toxicol 41:877–906

    Article  CAS  PubMed  Google Scholar 

  • Teixeira RM, Santos ARS, Ribeiro SJ, Calixto JB, Rae GA, De Lima TCM (1996) Effects of central administration of tachykinin receptor agonists and antagonists on plus-maze behavior in mice. Eur J Pharmacol 311:7–14

    Article  CAS  PubMed  Google Scholar 

  • Treit D, Menard J, Royan C (1993) Anxiogenic stimuli in the elevated plus-maze. Pharmacol Biochem Behav 44:463–469

    Article  CAS  PubMed  Google Scholar 

  • van de Wetering BJM, van den Heuvel OA, Pauls DL (1999) The genetics of anxiety disorders. Acta Neuropsychiatr 11:63–66

    Article  Google Scholar 

  • Varty GB, Cohen-Williams ME, Morgan CA, Pylak U, Duff RA, Lachowicz JE, Carey GJ, Coffin VL (2002) The gerbil elevated plus-maze II: Anxiolytic-like effects of selective neurokinin NK1 receptor antagonists. Neuropsychopharmacology 27:357–370

    Article  CAS  PubMed  Google Scholar 

  • Vassout A, Veenstra S, Hauser K, Ofner S, Brugger F, Schilling W, Gentsch C (2000) NKP608: a selective NK-1 receptor antagonist with anxiolytic-like effects in the social interaction and social exploration test in rats. Reg Pept 96:7–16

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank Dr. Conrad Gentsch from Pharma Novartis in Basel for providing to us NKP608. A. Ramos and R.N. Takahashi had fellowships from CNPq. L.F. Vendruscolo had a scholarship from CAPES. G.R. Brüske had a scholarship from PIBIC-CNPq.

Author information

Authors and Affiliations

  1. Laboratório de Genética do Comportamento, Departamento de Biologia Celular, Embriologia e Genética, Universidade Federal de Santa Catarina, 88.040-900, Florianópolis SC, Brazil

    Gustavo R. Brüske & André Ramos

  2. Departamento de Farmacologia, Universidade Federal de Santa Catarina, 88.040-900, Florianópolis SC, Brazil

    Leandro F. Vendruscolo & Reinaldo N. Takahashi

Authors
  1. Leandro F. Vendruscolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Reinaldo N. Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gustavo R. Brüske
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. André Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to André Ramos.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vendruscolo, L.F., Takahashi, R.N., Brüske, G.R. et al. Evaluation of the anxiolytic-like effect of NKP608, a NK1-receptor antagonist, in two rat strains that differ in anxiety-related behaviors. Psychopharmacology 170, 287–293 (2003). https://doi.org/10.1007/s00213-003-1545-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1545-4

Keywords

Search

Navigation