Advertisement

Psychopharmacology

, Volume 121, Issue 2, pp 186–191 | Cite as

The anxiolytic-like activity of GR159897, a non-peptide NK2 receptor antagonist, in rodent and primate models of anxiety

  • D. M. Walsh
  • S. C. Stratton
  • F. J. Harvey
  • I. J. M. Beresford
  • R. M. Hagan
Original Investigation

Abstract

The non-peptide NK2 receptor antagonist, GR159897, was evaluated in two putative models of anxiety, the mouse light-dark box and the marmoset human intruder response test. Effects were compared to the structurally dissimilar NK2 antagonist, (±) SR48968 and the benzodiazepines, diazepam and chlordiazepoxide. GR159897 (0.0005–50 µg/kg SC) caused significant and dose-dependent increases in the amount of time mice spent in the more aversive light compartment of the light-dark box, with no effect on locomotor activity. (±)SR48968 (0.0005–0.5 µg/kg SC) and diazepam (1–1.75 mg/kg SC), also increased time spent in the light compartment, without effect on locomotor activity. In the marmoset human intruder response test, GR159897 (0.2–50 µg/kg SC) significantly increased the amount of time marmosets spent at the front of the cage during confrontation with a human observer (“threat”). Similar effects were produced by (±)SR48968 (10–50 µg/kg SC) and chlordiazepoxide (0.3–3.0 mg/kg SC). These results provide further evidence, in both rodent and primate species, for the ability of NK2 antagonists to restore behaviours which have been suppressed by novel aversive environments. Such effects indicate that NK2 antagonists may have anxiolytic activity.

Key words

GR159897 Tachykinin NK2 receptor antagonist Anxiety Mouse light-dark box Marmoset human intruder response test Tachykinin Neurokinin A 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ball DI, Beresford IJM, Wren GPA, Pendry YD, Sheldrick RLG, Walsh DM, Turpin MP, Hagan RM, Coleman RA (1994) In vitro and in-vivo pharmacology of the non-peptide antagonist at tachykinin NK2-receptors, GR159897. Br J Pharmacol 112:48PGoogle Scholar
  2. Barden N, Daigle M, Picard V, Di Paolo T (1983) Perturbation of rat brain serotonergic systems results in an inverse relation between substance P and serotonin concentrations measured in discrete nuclei. J Neurochem 41:834–840Google Scholar
  3. Beresford IJM, Sheldrick RLG, Ball DI, Turpin MP, Walsh DM, Hawcock AB, Coleman RA, Hagan RM, Tyers MB (1995) GR159897, a potent non-peptide antagonist at tachykinin NK2 receptors. Eur J pharmacol 272:241–248Google Scholar
  4. Bradwejn J, Koszycki D, Du Tertre AC, Van Megen H, Den Boer J, Westenberg H, Annable L (1994) The panicogenic effects of cholecystokinin-tetrapeptide are antagonized by L-365,260, a central cholecystokinin receptor antagonist, in patients with a panic disorder. Arch Gen Psychiatry 51:486–493Google Scholar
  5. Cooper AWJ, Adams HS, Bell R, Gore PM, McElroy AB, Pritchard JM, Smith PW, Ward P (1994) GR159897 and related analogues as highly potent, orally active non-peptide neurokinin NK2 receptor antagonists. Bioorganic Med Chem Lett 4:1951–1956Google Scholar
  6. Costall B, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ (1988) Zacopride: anxiolytic profile in rodent and primate models of anxiety. J Pharm Pharmacol 40:302–305Google Scholar
  7. Costall B, Jones BJ, Kelly ME, Naylor RJ, Tomkins DM (1989) Exploration of mice in a black and white test box: validation as a model of anxiety. Pharmacol Biochem Behav 32:777–785Google Scholar
  8. Costall B, Domeney AM, Gerrard PA, Horovitz ZP, Kelly ME, Naylor RJ, Tomkins DM (1990) Effects of captopril and SQ29,852 on anxiety-related behaviours in rodent and marmoset. Pharmacol Biochem Behav 36:13–20Google Scholar
  9. Costall B, Naylor RJ (1992) Serotonin and psychiatric disorders. A key to new therapeutic approaches. Arzneim Helforschung 42:246–249Google Scholar
  10. Crawley J, Goodwin FK (1980) Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines. Pharmacol Biochem Behav 13:167–170Google Scholar
  11. Dorow R, Horowski R, Paschelke G, Amin M, Braestrup C (1983) Severe anxiety induced by FG7142, a β-carboline ligand for benzodiazepine receptors. Lancet 41:98–99Google Scholar
  12. Elliott PJ, Mason GS, Stephens-Smith M, Hagan RM (1991) Behavioural and biochemical responses following activation of midbrain dopamine pathways by receptor selective neurokinin agonists. Neuropeptides 19:119–126Google Scholar
  13. Emonds-Alt X, Vilain P, Goulaouic P, Proietto V, Van Broeck D, Advenier C, Naline E, Neliat G, Le Fur G, Breliere J-C (1992) A potent and selective non-peptide antagonist of the neurokinin A (NK2) receptor. Life Sci 50:PL101-PL106Google Scholar
  14. Forchetti CM, Marco EJ, Meek JL (1982) Serotonin and gamma-aminobutyric acid turnover after injection into the median raphe of substance P andd-ala-metenkephalinamide. J Neurochem 28:1336–1341Google Scholar
  15. Guard S, Zarnegar R, Watling KJ, Quirion R, Takeda Y, Krause JE (1991) [125I]Neuropeptide-γ and [125I]iodohistidyl-neurokinin A label multiple tachykinin receptors in rat brain. Br J Pharmacol 104:229PGoogle Scholar
  16. Hagan RM, Ireland SJ, Jordan CC, Beresford IJM, Deal MJ, Ward P (1991) Receptor-selective, peptidase-resistant agonists at neurokinin NK1 and NK2 receptors: new tools for investigating neurokinin function. Neuropeptides 19:127–135Google Scholar
  17. Hagan RM, Beresford IJM, Stables JS, Dupere J, Stubbs CM, Elliott PJ, Sheldrick RLG, Chollet A, Kawashima E, McElroy AB, Ward P (1993) Characterisation, CNS distribution and function of NK2 receptors studied using potent NK2 receptor antagonists. Regul Pept 46:9–19Google Scholar
  18. Higgins GA, Bradbury AJ, Jones BJ, Oakley NR (1988) Behavioural and biochemical consequences following activation of 5-HT1-like and GABA receptors in the dorsal raphe nucleus of the rat. Neuropharmacology 27:993–1001Google Scholar
  19. Hjorth S, Carlsson A, Lindberg P, Sanchez D, Wikstrom H, Arvidsson LE, Hacksell U, Nilsson JLG (1982) 8-Hydroxy-2-(di-n Propylamino) tetralin, 8-OHDPAT, a potent and selective simplified ergot congener with central 5-HT receptor stimulating activity. J Neural Transm 55:169–188Google Scholar
  20. Hughes J, Boden P, Costall B, Domeney AM, Kelly E, Horwell DC, Hunter JC, Pinnock RD, Woodruff GN (1990) Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci USA 87:6728–6732Google Scholar
  21. Jones BJ, Costall B, Domeney AM, Kelly ME, Naylor RJ, Oakley NR, Tyers MB (1988) The potential anxiolytic activity of GR38032F, a 5-HT3-receptor antagonist. Br J Pharmacol 93:985–993Google Scholar
  22. Maggi CA, Patacchini R, Rovero P, Giachetti A (1993) Tachykinin receptors and tachykinin receptor antagonists. J Auton Pharmacol 13:23–93Google Scholar
  23. Magoul R, Onteniente B, Oblin A, Calas A (1986) Inter-and intracellular relationship of substance P-containing neurons with serotonin and GABA in the dorsal raphe nucleus: combination of autoradiographic and immunocytochemical techniques. J Histochem Cytochem 34:735–742Google Scholar
  24. Mussap CJ, Geraghty DP, Burcher E (1993) Tachykinin receptors: a radioligand binding perspective. J Neurochem 60:1987–2009Google Scholar
  25. Overton P, Elliott PJ, Hagan RM, Clark D (1992) Neurokinin agonists differentially affect A9 and A10 dopamine cells in the rat. Eur J Pharmacol 213:165–166Google Scholar
  26. Santucci V, Gueudet C, Emonds-Alt X, Breliere J-C, Soubrie P, Le Fur G (1993) The NK2 receptor antagonist SR48968 inhibits thalamic responses evoked by thermal but not mechanical nociception. Eur J Pharmacol 237:43–146Google Scholar
  27. Stratton SC, Beresford IJM, Elliott PJ, Hagan RM (1993a) Behavioural effects of centrally infused tachykinin NK2 receptor agonists and antagonists in rat models of anxiety. J Psychopharmacol 7:suppl A11Google Scholar
  28. Stratton SC, Beresford IJM, Harvey FJ, Turpin MP, Hagan RM, Tyers MB (1993b) Anxiolytic activity of tachykinin NK2 receptor antagonists in the mouse light-dark box. Eur J Pharmacol 250:R11-R12Google Scholar
  29. Stratton SC, Beresford IJM, Hagan RM (1994) GR159897, a potent non-peptide tachykinin NK2 receptor antagonist, releases suppressed behaviours in a novel aversive environment. Br J Pharmacol 112:49PGoogle Scholar
  30. Vincent SR, Staines WA, McGeer EG, Fibiger HC (1980) Transmitters contained in the efferents of the habenula. Brain Res 195:479–484Google Scholar
  31. Walsh DM, Elliott PJ, Hagan RM (1992) Role of NK-2 receptors in the antidipsogenic activity of neurokinins in the mouse. Gen Pharmacol 23:231–233Google Scholar
  32. Walsh DM, Beresford IJM, Hagan RM (1994) Profile of GR 159897, a potent non-peptide tachykinin NK2 receptor antagonist in a primate intruder response model. Br J Pharmacol 112:332PGoogle Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • D. M. Walsh
    • 1
  • S. C. Stratton
    • 1
  • F. J. Harvey
    • 1
  • I. J. M. Beresford
    • 1
  • R. M. Hagan
    • 1
  1. 1.Department of Pharmacology, Glaxo Research & Development Ltd.Medicines Research CentreStevenageUK

Personalised recommendations