, Volume 101, Issue 2, pp 244–249 | Cite as

Chronic administration of the 5-HT3 receptor antagonist BRL 43694; effects on reflex epilepsy and social behaviour of the Mongolian gerbil

  • Margaret G. Cutler
  • David C. Piper
Original Investigations


The 5-HT3 receptor antagonist BRL 43694 was administered in drinking fluid to Mongolian gerbils, previously selected for their propensity to exhibit seizures on mild stimulation, for 11 days at doses of 1.5 µg/kg, 150 µg/kg and 1 mg/kg daily, while controls received tap water. Effects upon behaviour during encounters under white light with an untreated resident gerbil were assessed using ethological procedures. Effects upon seizure susceptibility and severity were also examined. All doses of BRL 43694 significantly increased the time spent by gerbils in the social activity “attend”, and acts of social investigation involving physical contact between animals were significantly increased only by the highest dose of 1 mg/kg, as was occurrence of the specific element, “groom”. The duration of flight was increased in gerbils receiving the drugs at 1.5 µg/kg. The treatment had no effect upon seizure susceptibility or severity. It is suggested that BRL 43694 increases the sensitivity of gerbils to their social environment. At the lower dose this was seen as an increase in flight, at all doses it was associated with increase of the social activity “attend” and at the high dose it was manifested as an increase in active social interaction. Further investigations are required to assess the relevance of these findings to the purported anxiolytic activity of 5-HT3 receptor antagonists.

Key words

5-HT3 receptor antagonist BRL 43694 Gerbil Social interaction Seizure susceptibility 


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  1. Barnes JM, Barnes NM, Costall B, Naylor RJ, Tyers MB (1989) 5-HT3 receptors mediate inhibition of (3H)acetylcholine release from rat entorhinal cortex in vitro. Br J Pharmacol 98:773 pGoogle Scholar
  2. Bradley PB, Engel G, Feniuk W, Fozard JR, Humphrey PPA, Middlemiss DN, Mylecharane EJ, Richardson BP, Saxena PR (1986) Proposals for the classification and nomenclature of functional receptors for 5-hydrotryptamine. Neuropharmacology 25:563–576Google Scholar
  3. Chance MRA (1984) Biological systems synthesis of mentality and the nature of the two modes of mental operation: hedonic and agonic. Man-Environ Sys 14:143–157Google Scholar
  4. Chapman JB (1986) Anticonvulsant drugs: effects on development and behaviour in mice and gerbils. PhD Thesis, CNAAGoogle Scholar
  5. Chapman JB, Cutler MG (1983) Behavioural effects of phenobarbitone. 1. Effects in the offspring of laboratory mice. Psychopharmacology 79:155–160Google Scholar
  6. Chapman JB, Cutler MG (1984) Sodium valproate: effects on social behaviour and physical development in the mouse. Psychopharmacology 83:390–396Google Scholar
  7. Chapman JB, Cutler MG (1989) Effects of sodium valproate on development and social behaviour in the Mongolian gerbil. Neurotoxicol Teratol 11:193–198Google Scholar
  8. Costall B, Domeney AM, Kelly ME, Naylor RJ, Tyers MB (1987a) The behavioural consequences of treatment with selective 5-HT3 receptor antagonists. Br J Pharmacol 92:657Google Scholar
  9. Costall B, Domeney AM, Kelly ME, Naylor RJ, Tyers MB (1987b) The antipsychotic potential of GR 38032F, a selective antagonist of 5-HT3 receptors in the central nervous system. Br J Pharmacol 92:89 pGoogle Scholar
  10. Costall B, Domeney AM, Naylor RJ, Tyers MB (1987c) Effects of the 5-HT3 receptor antagonist, GR 38032 F, on raised dopaminergic activity in the mesolimbic system of the rat and marmoset brain. Br J Pharmacol 92:881–894Google Scholar
  11. Costall B, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ (1988a) Zacopride: anxiolytic profile in rodent and primate models of anxiety. J Pharm Pharmacol 40:302–305Google Scholar
  12. Costall B, Domeney AM, Jones BJ, Kelly ME, Gerrard PA, Naylor PJ, Tyers MB (1988b) Influence of GR 38032F on the behavioural consequences of ceasing subchronic treatment with drugs of abuse. Br J Pharmacol 96:905Google Scholar
  13. Costall B, Coughlan J, Kelly ME, Naylor RJ, Tyers MB (1989) Scopolamine-induced deficits in a T-maze reinforced alternation task are attenuated by 5-HT3 receptor antagonists. Br J Pharmacol 97:475 pGoogle Scholar
  14. Cunningham D, Hawthorn J, Pople A, Gazet J-C, Ford HT, Challoner T, Combes RC (1987) Prevention of emesis in patients receiving cytotoxic drugs by GR 38032F, a selective 5-HT3 receptor antagonist. Lancet I:1461–1463Google Scholar
  15. Cutler MG, Dixon AK (1988) Effects of the 5-HT3 antagonist, ICS 205–930, on behaviour of mice during social encounters. Br J Pharmacol 96:12Google Scholar
  16. Cutler MG, Horton RW (1988) Paradoxical enhancement of seizures in the gerbil after chronic treatment with sodium valproate. Neuropharmacology 27:617–621Google Scholar
  17. Cutler MG, Mackintosh JH (1989) Epilepsy and behaviour of the Mongolian gerbil; an ethological study. Physiol Behav 46:561–566Google Scholar
  18. Dixon AK (1986) Ethological aspects of psychiatry. Arch Suisses Neurol Psychiatry 137:151–163Google Scholar
  19. Feuerstein TJ, Hertting G (1986) Serotonin (5-HT) enhances hippocampal noradrenaline (NA) release: evidence for facilitatory 5-HT receptors within the CNS. Naunyn Schiedebergs Arch Pharmacol 333:191–197Google Scholar
  20. File SE (1980) The role of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J Neuroci Methods 2:219–238Google Scholar
  21. Fozard JR (1984) Neuronal 5-HT receptors in the periphery. Neuropharmacology 23:1473–1486Google Scholar
  22. Frey HH, Loscher W, Reiche R, Schultz D (1983) Anticonvulsant potency of common antiepileptic drugs in the gerbil. Pharmacology 27:330–335Google Scholar
  23. Hagan RM, Butler A, Hill JM, Jordan CC, Ireland SJ, Tyers MB (1987) Effect of the 5-HT3 receptor antagonist, GR 38032F, on responses to injection of a neurokinin agonist into the ventral tegmental area of rat brain. Eur J Pharmacol 138:303–305Google Scholar
  24. Hoyer D, Waeber C, Neijt HC, Palacios JM (1989) 5-HT3 recognition sites in the central and peripheral nervous system: autoradiographic and radioligand binding studies. Br J Pharmacol 96:7Google Scholar
  25. Johnston AL, File SE (1988) Effects of 5-HT3 antagonists in two animal tests of anxiety. Neurosci Lett [Suppl] 32:544Google Scholar
  26. Jones BJ, Oakley NR, Tyers MB (1987) The anxiolytic activity of GR 38032F, a 5-HT3 receptor antagonist, in the rat and cynomolgus monkey. Br J Pharmacol 90:88Google Scholar
  27. Jones BJ, Costall B, Domeney AM, Kelly ME, Naylor RJ, Oakley NR, Tyers MB (1988) The potential anxiolytic activity of GR 38032F, a 5-HT3 receptor antagonist. Br J Pharmacol 93:985–993Google Scholar
  28. Kilpatrick GJ, Jones BJ, Tyers MB (1987) Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature 330:746–748Google Scholar
  29. Loscher W (1985) Anticonvulsant action in the epileptic gerbil of novel inhibitors of GABA uptake. Eur J Pharmacol 110:103–108Google Scholar
  30. Loskota WJ, Lomax P, Rich ST (1974) The gerbil as a model for the study of the epilepsies. Seizure patterns and ontogenesis. Epilepsia 15:109–119Google Scholar
  31. Mackintosh JH, Silverman AP, Chance MRA (1977) The contribution of ethological techniques to the study of drug effects. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology vol 7. Plenum Press, London, pp 3–35Google Scholar
  32. Majkowski J, Kaplan H (1983) Value of Mongolian gerbils in antiepileptic drug evaluation. Epilepsia 24:609–615Google Scholar
  33. Miczek KA (1982) Ethological analysis of drug action on aggression, defense and defeat. In: Spiegelstein MY, Levy A (eds) Behavioural models and the analysis of drug action. Elsevier, Amsterdam, pp 225–239Google Scholar
  34. Peterson GM, Ribak CE (1987) Hippocampus of the seizure sensitive gerbil is a specific site for anatomical changes in the GABA-ergic system. J Comp Neurol 261:405–422Google Scholar
  35. Piper D, Upton N, Thomas D, Nicholass J (1988) The effects of the 5-HT3 receptor antagonists BRL 43694 and GR 38032F in animal behavioural models of anxiety. Br J Pharmacol 94:314Google Scholar
  36. Ribak CE, Khan SU (1987) The effects of knife cuts of hippocampal pathways on epileptic activity in the seizure sensitive gerbil. Brain Res 418:146–151Google Scholar
  37. Richardson BP, Engel G, Donatsch P, Stadler PA (1985) Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature 316:126–131Google Scholar
  38. Thiessen DD, Lindzey G, Friend HC (1968) Spontaneous seizures in the Mongolian gerbil (Meriones unguiculatus). Psychon Sci 11:227–228Google Scholar
  39. Wallis D (1981) Neuronal 5-hydroxytryptamine receptors outside the central nervous system. Life Sci 29:2345–2355Google Scholar
  40. Watling KJ, Aspley S, Swain CJ, Saunders J (1988) Tritiated quaternized ICS 205–930 labels 5-HT3 binding sites in rat brain. Eur J Pharmacol 149:397–398Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • Margaret G. Cutler
    • 1
  • David C. Piper
    • 2
  1. 1.Department of Biological SciencesGlasgow CollegeGlasgowUK
  2. 2.Beecham PharmaceuticalsHarlow, EssexUK

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