, Volume 110, Issue 1–2, pp 53–59 | Cite as

The role of serotonergic mechanisms in inhibition of isolation-induced aggression in male mice

  • Connie Sánchez
  • Jørn Arnt
  • John Hyttel
  • Ejner K. Moltzen
Original Investigations


The role of serotonergic (5-HT) receptor subtypes in mediation of aggressive behaviour in isolated male mice has been studied. Increase of attack latency was used as a simple measure of antiaggressive behaviour. 5-HT1A agonists (BAY R 1531, 8-OHDPAT, flesinoxan, gepirone, 5MeO DMT, buspirone, ipsapirone, BMY 14802) completely inhibit the aggressive behaviour irrespective of their intrinsic activities. Also the putative antagonists spiroxatrine and NAN 190 as well as the non-selective 5-HT1 agonists RU 24969, TFMPP, mCPP and eltoprazine have an antiaggressive effect. The mixed 5-HT1A andβ-adrenoceptor antagonists (−)-alprenolol and pindolol are ineffective and do not inhibit the effect of 8-OHDPAT. Neither does the non-selective 5-HT antagonist metergoline. The antiaggressive effect correlates with 5-HT1A receptor affinity in vitro and with generalization to the 8-OHDPAT-induced discriminative stimulus. The selective 5-HT uptake inhibitor citalopram does not inhibit aggressive behaviour. The 5-HT2 agonist DOI has an antiaggressive effect only at high doses, whereas the 5-HT2 antagonist ritanserin and the 5-HT3 antagonist ondansetron are ineffective. Prazosin (α1-adrenoceptor antagonist), clonidine (α2-adrenoceptor agonist), clenbuterol (β-adrenoceptor agonist), ketanserin (5-HT2 receptor andα1-adrenoceptor antagonist), clozapine and (−)-octoclothepin (dopamine (DA), 5-HT2 receptor andα1-adrenoceptor antagonist) all show an antiaggressive effect. SCH 23390 (DA D1 receptor antagonist) and emonapride (DA D2 receptor antagonist) are ineffective. In conclusion, 5-HT1A receptors are involved in mediation of isolation-induced aggressive behaviour in mice. The involvement of other 5-HT receptor subtypes needs further clarification. The adrenergic system may also be involved. DA antagonists are ineffective.

Key words

Aggression Isolation-induced Mice Serotonin 5-HT Drug discrimination 


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  1. Arnt J (1989) Characterization of the discriminative stimulus properties Induced by 5-HT1 and 5-HT2 agonists in rats. Pharmacol Toxicol 64:165–172Google Scholar
  2. Arnt J, Hyttel J (1989) Facilitation of 8-OHDPAT-induced forepaw treading of rats by the 5-HT2 agonist DOI. Eur J Pharmacol 161:45–51Google Scholar
  3. Arnt J, Hyttel J, Perregaard J (1987) Dopamine D1 receptor agonists combined with the selective D2 agonist quinpirole facilitate the expression of oral stereotyped behaviour in rats. Eur J Pharmacol 133:137–145Google Scholar
  4. Barrett JE, Hoffmann SM, Olmstead SN, Foust MJ, Harrod C, Weissman BA (1989) Behavioral and neurochemical effects of the serotonin (5-HT)1A receptor ligand spiroxatrine. Psychopharmacology 97:319–325Google Scholar
  5. Burn JH, Finney DJ, Goodwin LG (1952) Biological standardization. Oxford University Press, London, New York, Toronto, pp 114Google Scholar
  6. Coccaro EF, Gabriel S, Siever LJ (1990) Buspirone challenge: preliminary evidence for a role for central 5-HT1A receptor function in impulsive aggressive behavior in humans. Psychopharm Bull 26 [3]:393–405Google Scholar
  7. Costain DW, Green AR (1978)β-adrenoceptor antagonists inhibit the behavioural responses of rats to increased brain 5-hydroxytryptamine. Br J Pharmacol 64:193–200Google Scholar
  8. Cowen PJ, Grahame-Smith DG, Green AR, Heal DJ (1982)β-Adrenoceptor agonists enhance 5-hydroxytryptamine-mediated behavioural responses. Br J Pharmacol 76:265–270Google Scholar
  9. Crawley JN, Contrera JF (1976) Intraventricular 6-hydroxydopamine lowers isolation-induced fighting behavior in male mice. Pharmacol Biochem Behav 4:381–384Google Scholar
  10. Cunningham KA, Appel JB (1986) Possible 5-hydroxytryptamine1 (5-HT1) receptor involvement in the stimulus properties of 1-(m-trifluoromethylphenyl)-piperazine (TFMPP). J Pharmacol Exp Ther 237:369–377Google Scholar
  11. DaVanzo JP, Daugherty M, Ruckart R and Kang L (1966) Pharmacological and biochemical studies in isolation-induced fighting mice. Psychopharmacologia 9:210–219Google Scholar
  12. Eichelman BS (1990) Neurochemical and psychopharmacologic aspects of aggressive behavior. Annu Rev Med 41:149–158Google Scholar
  13. Glennon RA (1987) Central serotonin receptors as targets for drug research. J Med Chem 30:1–12Google Scholar
  14. Glennon RA, McKenney JD, Young R (1984) Discriminative stimulus properties of the serotonin agonist 1-(3-trifluoromethylphenyl) piperazine (TFMPP). Life Sci 35:1475–1480Google Scholar
  15. Glennon RA, Naiman NA, Pierson ME, Titeler M, Lyon RA, Weisberg E (1988) NAN-190: an arylpiperazine analog that antagonizes the stimulus effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT). Eur J Pharmacol 154:339–341Google Scholar
  16. Goodwin GM, De Souza RJ, Green AR (1985) The pharmacology of the hypothermia response in mice to 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT). Neuropharmacology 24:1187–1194Google Scholar
  17. Grant EC, Mackintosh JH (1963) A comparison of the social postures of some laboratory rodents. Behaviour 21:246–259Google Scholar
  18. Hamon M, Cossery J-M, Spampinato U, Gozlan H (1986) Are there selective ligands for 5-HT1A and 5-HT1B receptor binding sites in brain? TIPS Sept. 336–337Google Scholar
  19. Hjorth S, Carlsson A (1986) Is pindolol a mixed agonist-antagonist at central serotonin (5-HT) receptors? Eur J Pharmacol 129:131–138Google Scholar
  20. Hjorth S, Sharp T (1990) Mixed agonist/antagonist properties of NAN-190 at 5-HT1A receptors: behavioural and in vivo brain microdialysis studies. Life Sci 46:955–963Google Scholar
  21. Hyttel J, Bøgesø K, Lembøl HL, Larsen J-J, Meier E (1988) Neurochemical profile in vitro of irindalone: a 5-HT2-receptor antagonist. Drug Dev Res 15:389–404Google Scholar
  22. Kennett GA, Curzon G (1988) Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors. Br J Pharmacol 94:137–147Google Scholar
  23. Malick JB, Barnett A (1976) The role of serotonergic pathways in isolation-induced aggression in mice. Pharmacol Biochem Behav 5:55–61Google Scholar
  24. McMillen BA, Scott SM, Williams HL, Sanghera MK (1987) Effects of gepirone, an aryl-piperazine anxiolytic drug, on aggressive behavior and brain monoaminergic neurotransmission. Naunyn-Schmiedeberg's Arch Pharmacol 335:454–464Google Scholar
  25. McMillen BA, DaVanzo EA, Scott SM, Song AH (1988) N-alkyl-substituted aryl-piperazine drugs: relationship between affinity for serotonin receptors and inhibition of aggression. Drug Dev Res 12:53–62Google Scholar
  26. McMillen BA, DaVanzo EA, Song AH, Scott SM, Rodriguez ME (1989) Effects of classical and atypical antipsychotic drugs on isolation-induced aggression in male mice. Eur J Pharmacol 160:149–153Google Scholar
  27. Meller E, Goldstein M, Bohmaker K (1989) Receptor reserve for 5-hydroxytryptamine1A-mediated inhibition of serotonin synthesis: possible relationship to anxiolytic properties of 5-hydroxytryptamine1A agonists. Mol Pharmacol 37:231–237Google Scholar
  28. Miczek KA, Donat P (1987) Brain 5-HT system and inhibition of aggressive behaviour. In: Bevan P, Cools AR, Archer T (eds) Behavioural pharmacology of 5-HT. Erlbaum, Hillsdale, NJ, pp 117–144Google Scholar
  29. Middlemiss DN (1986) Blockade of the central 5-HT autoreceptor byβ-adrenoceptor antagonists. Eur J Pharmacol 120:51–56Google Scholar
  30. Modigh K (1973) Effects of isolation and fighting in mice on the rate of synthesis of noradrenaline, dopamine and 5-hydroxytryptamine in the brain. Psychopharmacologia 33:1–17Google Scholar
  31. Nielsen EB, Jepsen SA (1985) Antagonism of the amphetamine cue by both classical and atypical antipsychotic drugs. Eur J Pharmacol 111:167–176Google Scholar
  32. Nimgaonkar VL, Green AR, Cowen PJ, Heal DJ, Grahame-Smith DG, Deakin JFW (1983) Studies on the mechanisms by which clenbuterol, aβ-adrenoceptor agonist, enhances 5-HT-mediated behaviour and increases metabolism of 5-HT in the brain of the rat. Neuropharmacology 22:739–749Google Scholar
  33. Ögren S-O, Holm A-C, Renyi AL, Ross SB (1980) Anti-aggressive effect of zimelidine in isolated mice. Acta Pharmacol Toxicol 47:71–74Google Scholar
  34. Olivier B, Mos J (1988) Serotonin, serenics and aggressive behaviour in animals. In: Swinkels JA, Blijleven W (eds) Depression, anxiety and aggression. Factors that influence the course. Medidact, Houten, pp 133–165Google Scholar
  35. Olivier B, Mos J, van der Heyden J, Hartog J (1989) Serotonergic modulation of social interactions in isolated male mice. Psychopharmacology 97:154–156Google Scholar
  36. Olivier B, Mos J, Rasmussen D (1990) Behavioural pharmacology of the serenic, eltoprazine. Drug Metab Drug Interact 8 [1–2]:31–83Google Scholar
  37. Schuurman T, Glaser DG, Spencer Jr, Traber J (1987) Neurochemical and behavioural effects of the new 5-HT1A receptor ligand BAY R 1531. Behavioural pharmacology of 5-HT. International Conference under auspices of the European Behavioural Pharmacology Society Nov: 36Google Scholar
  38. Sijbesma H, Schipper J, de Kloet ER, Mos J, van Aken H, Olivier B (1991) Postsynaptic 5-HT1 receptors and offensive aggression in rats: a combined behavioural and autoradiographic study with eltoprazine. Pharmacol Biochem Behav 38:447–458Google Scholar
  39. Traber J, Glaser T (1987) 5-HT1A receptor-related anxiolytics. TIPS Nov. [8]:432–437Google Scholar
  40. Tricklebank MD, Middlemiss DN, Neill J (1986) Pharmacological analysis of the behavioural and thermoregulatory effects of the putative 5-HT1 receptor agonist, RU 24969, in the rat. Neuropharmacology 25 [8]:877–886Google Scholar
  41. Tukey JW (1949) Comparing individual means in the analysis of variance. Biometrics 5:99Google Scholar
  42. Valzelli L (1969) Aggressive behaviour induced by isolation. In: Garattini S, Sigg AB (eds) Aggressive behaviour. Excerpta Medica, Amsterdam, pp 70–76Google Scholar
  43. Valzelli L, Bernasconi S (1979) Aggressiveness by isolation and brain serotonin turnover changes in different strains of mice. Neuropsychobiology 5:129–135Google Scholar
  44. Weinstock M, Weiss C (1980) Antagonism by propranolol of isolation-induced aggression in mice: correlation with 5-hydroxytryptamine receptor blockade. Neuropharmacology 49:653–656Google Scholar
  45. Yen CY, Stanger RL, Millnam N (1959) Ataractic suppression of isolation-induced aggressive behaviour. Arch Int Pharmacodyn Ther 123:179–185Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Connie Sánchez
    • 1
  • Jørn Arnt
    • 1
  • John Hyttel
    • 1
  • Ejner K. Moltzen
    • 2
  1. 1.Pharmacological ResearchH. Lundbeck A/SValbyDenmark
  2. 2.Department of Medicinal ChemistryH. Lundbeck A/SValbyDenmark

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