Skip to main content
SpringerLink
Log in

Differential modulation of antipredator defensive behavior in Swiss-Webster mice following acute or chronic administration of imipramine and fluoxetine

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

Abstract

The Mouse Defense Test Battery (MDTB) has been designed to assess defensive reactions in Swiss-Webster mice to situations associated with a natural predator, the rat. Primary measures taken before, during and after predator confrontation comprise escape attempts, predator assessment, defensive attack and flight. Previous reports from this laboratory have shown that the panic-promoting drug yohimbine potentiated flight behavior, while long-term treatment with the panicolytic agent alprazolam reduced this response. In order to evaluate further the possibility that the MDTB may represent an effective animal model of panic attacks, the present study investigated the behavioral effect of imipramine and fluoxetine, two serotonin reuptake inhibitors (SRIs) known to alleviate panic symptoms when given on a repeated basis. Both drugs were administered acutely and chronically (one daily IP injection for 21 days) at 5, 10 and 15 mg/kg. Our results showed that a single dose of imipramine or fluoxetine strongly potentiated flight reactions in response to an approaching predator and increased defensive attack toward the rat. This was in contrast to chronic treatment with each drug which dramatically decreased flight responses and defensive attack behaviors. In addition, long-term administration with both SRIs produced a reliable attenuation of predator assessment activities. Taken together, these findings suggest an acute anxiogenic-like effect of imipramine and fluoxetine followed by a fear/anxiety reducing effect after repeated administrations. These results support clinical observations revealing an acute anxiogenic effect of SRIs followed by an anxiolytic and/or panicolytic effect after chronic use, and support previous results suggesting that the MDTB may be useful for the investigation of panic-modulating agents.

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

Similar content being viewed by others

References

  • Audi EA, de Aguiar JC, Graeff FG (1988) Mediation by serotonin of the antiaversive effect of zimelidine and propranolol injected into the dorsal midbrain central grey. J Psychopharmacol 2:26–32

    Google Scholar 

  • Blanchard DC, Rodgers RJ, Hendrie CA, Hori K (1988) “Taming” of wild rats (Rattus rattus) by 5-HT1A agonists buspirone and gepirone. Pharmacol Biochem Behav 31:269–278

    Google Scholar 

  • Blanchard DC, Hori K, Rodgers RJ, Hendrie CA, Blanchard RJ (1989) Attenuation of defensive threat and attack in wild rats (Rattus rattus) by benzodiazepines. Psychopharmacology 97:392–401

    Google Scholar 

  • Blanchard RJ, Blanchard DC, Weiss SM (1990) Ethanol effects in an anxiety/defense test battery. Alcohol 7:375–381

    Google Scholar 

  • Blanchard RJ, Shepherd JK, Rodgers RJ, Magee L, Blanchard DC (1993a) Attenuation of antipredator defensive behavior in rats following chronic treatment with imipramine. Psychopharmacology 110:245–253

    Google Scholar 

  • Blanchard RJ, Taukulis HK, Rodgers RJ, Magee LK, Blanchard DC (1993b) Yohimbine potentiates active defensive responses to threatening stimuli in Swiss-Webster mice. Pharmacol Biochem Behav 44:673–681

    Google Scholar 

  • Bodnoff SR, Suranyi-Cadotte B, Aitken DH, Quirion R, Meaney MJ (1988) The effects of chronic antidepressant treatment in an animal model of anxiety. Psychopharmacology 95:298–302

    Google Scholar 

  • Bodnoff SR, Suranyi-Cadotte B, Quirion R, Meaney MJ (1989) A comparison of the effects of diazepam versus several typical and atypical anti-depressant drugs in an animal model of anxiety. Psychopharmacology 97:277–279

    Google Scholar 

  • Burnet PWJ, Michelson D, Smith MA, Gold PW, Sternberg EM (1994) The effect of chronic imipramine administration on the densities of 5-HT1A and 5-HT2 receptors and the abundancies of 5-HT receptor and transporter mRNA in the cortex, hip-pocampus and dorsal raphe of three strains of rat. Brain Res 638:311–324

    Google Scholar 

  • Cassella JV, Davis M (1985) Fear-enhanced acoustic startle is not attenuated by acute or chronic imipramine treatment in rats. Psychopharmacology 87:278–282

    Google Scholar 

  • Craft RM, Howard JL, Pollard GT (1988) Conditioned defensive burying as a model for identifying anxiolytics. Pharmacol Biochem Behav 30:775–780

    Google Scholar 

  • Deakin JFW, Graeff FG (1991) 5-HT and mechanisms of defense. J Psychopharmacol 5:305–315

    Google Scholar 

  • Deakin JFW, Guimaraes FS, Wang F, Hellewell J, Hensman R (1991) 5-HT receptor mechanisms in human anxiety. In: Briley M, File SE (eds) New concepts in anxiety. CRC Press, New York, pp 74–93

    Google Scholar 

  • Den Boer JA, Westenberg HGM (1990) Serotonin function in panic disorder: a double blind placebo controlled study with fluvoxamine and ritanserin. Psychopharmacology 102:85–94

    Google Scholar 

  • Dwyer KD, Roy EJ (1993) Juvenile desipramine reduces adult sensitivity to imipramine in two behavioral test. Pharmacol Biochem Behav 45:201–207

    Google Scholar 

  • Fontana DJ, Commissaris RL (1988) Effects of acute and chronic imipramine administration on conflict behavior in the rat: a potential “animal model” for study of panic disorder? Psychopharmacology 95:147–150

    Google Scholar 

  • Fuller RW (1993) Microdialysis studies with 5-HT reuptake inhibitors. Trends Pharmacol Sci 14:397

    Google Scholar 

  • Fuller RW (1994) Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis. Life Sci 55:163–167

    Google Scholar 

  • Garakani H, Zitrin CM, Klein DF (1984) Treatment of panic disorder with imipramine alone. Am J Psychiatry 141:446–448

    Google Scholar 

  • Giesecke ME (1990) Overcoming hypersensitivity of fluoxetine in a patient with panic disorder. Am J Psychiatry 147:532–533

    Google Scholar 

  • Gorman JM, Liebowitz MR, Fyer AJ, Goetz D, Campeas RB, Fyer MR, Davies SO, Klein DF (1987 An open trial of fluoxetine in the treatment of panic attacks. J Clin Psychopharmacol 7:329–332

    Google Scholar 

  • Graeff FG (1990) Brain defense system and anxiety. In: Burrows GD, Roth M, Noyes R Jr (eds) Handbook of anxiety, vol. 3. The neurobiology of anxiety. Elsevier, Amsterdam, pp 307–343

    Google Scholar 

  • Graeff FG (1991) Neurotransmitters in the dorsal periqueductual grey and animal models of panic anxiety. In: Briley M, File SE (eds) New concepts in anxiety CRC Press, New York, pp 288–307

    Google Scholar 

  • Graeff FG, Brandão ML, Audi EA, Schütz MTB (1986) Modulation of the brain aversive system by GABAergic and serotonergic mechanisms. Behav Brain Res 21:65–72

    Google Scholar 

  • Griebel G (1995) 5-Hydroxytryptamine-interacting drugs in animal models of anxiety disorders: more than 30 years of research. Pharmacol Ther:319–395

  • Griebel G, Blanchard RJ, Lee JC, Rodgers RJ, Blanchard DC (1994a) Attenuation of antipredator defensive behavior in Swiss-Webster mice following acute and chronic treatment with chlordiazepoxide and alprazolam. Soc Neurosci Abstr 20:811

    Google Scholar 

  • Griebel G, Moreau J-L, Jenck F, Misslin R, Martin JR (1994b) Acute and chronic treatment with 5-HT reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents. Psychopharmacology 113:463–470

    Google Scholar 

  • Griebel G, Blanchard DC, Jung A, Masuda CK, Blanchard RJ (1995a) 5-HT1A agonists modulate mouse antipredator defensive behavior differently than the preferential 5-HT2A antagonist pirenperone. Pharmacol Biochem Behav (in press)

  • Griebel G, Blanchard DC, Blanchard RJ (1995b) A model of “antipredator” defense in Swiss-Webster mice. Effects of benzodiazepine receptor ligands with different intrinsic activities. Behav Pharmacol (in press)

  • Hendrie CA, Neill JC (1991) An animal model of panic disorder. J Psychopharmacol 6:125 (abstract)

    Google Scholar 

  • Horn AS (1980) The mode of action of tricyclic antidepressants: a brief review of recent progress. Postgrad Med J 56 [Suppl 1]:9–12

    Google Scholar 

  • Humble M, Koczkas C, Wistedt B (1989) Serotonin and anxiety: an open study of citalopram in panic disorder. In: Stefanis CN, Soldatos CR, Rabavilas AD (eds) Psychiatry/Today: VIII World Congress of Psychiatry Abstracts. Elsevier, New York, p 151

    Google Scholar 

  • Jenck F, Broekkamp CLE, Van Delft AML (1989) Opposite control mediated by central 5-HT1A and non-5-HT1A (5-HT1B or 5-HT1C) receptors on periqueductal gray aversion. Eur J Pharmacol 161:219–221

    Google Scholar 

  • Kahn RS, Moore C (1993) Serotonin in the pathogenesis of anxiety. In: Hoehn-Saric R, McLeod DR (eds) Biology of anxiety disorders. American Psychiatric Press, Washington, pp 61–102

    Google Scholar 

  • Kahn RS, Westenberg HGM, Verhoeven WMA, Gispen de Wied CC, Mamerbeek WDJ (1987) Effect of a serotonin precursor and uptake inhibitor in anxiety disorders, a double blind comparison of 5-hydroxytryptophan, clomipramine and placebo. Int Clin Psychopharmacol 2:33–45

    Google Scholar 

  • Kahn RS, Van Praag HM, Wetzler S, Asnis GM, Barr G (1988) Serotonin and anxiety revisited. Biol Psychiatry 23:189–208

    Google Scholar 

  • Kilts CD, Commissaris RL, Rech RH (1981) Comparison of anticonflict drug effects in three experimental animal models of anxiety. Psychopharmacology 74:290–296

    Google Scholar 

  • Kiser RS, German DC, Lebowitz RM (1978) Serotonergic reduction of dorsal central gray area stimulation-produced aversion. Pharmacol Biochem Behav 9:27–31

    Google Scholar 

  • Klimek V, Zak Knapik J, Mackowiak M (1994) Effects of repeated treatment with fluoxetine and citalopram, 5-HT uptake inhibitors, on 5-HT1A and 5-HT2 receptors in the rat brain. J Psychiatry Neurosci 19:63–67

    Google Scholar 

  • Lister RG (1990) Ethologically-based animal models of anxiety disorders. Pharmacol Ther 46:321–340

    Google Scholar 

  • Mai J, Moryl E (1992) Effects of sertraline and citalopram given repeatedly on the responsiveness of 5-HT receptor subpopulations. J Neural Transm [GenSect] 88:143–156

    Google Scholar 

  • Martin P (1993) Effects of anxiolytic and antidepressant drugs in an animal model of panic. In: Hamon M, Ollat H, Thiébo MH (eds) Anxiety: neurobiology, clinical and therapeutic perspectives. John Libbey Eurotext Ltd, Paris pp 203–204

    Google Scholar 

  • Meert TF, Colpaert FC (1986) The shock probe conflict procedure. A new assay responsive to benzodiazepines, barbiturates and related compounds. Psychopharmacology 88:445–450

    Google Scholar 

  • Molewijk HE, Van der Poel, AM, Vedder AW, Olivier B (1993) Ultrasonic distress vocalisations in adult rats as a model for panic disorder. British Association for Psychopharmacology, 25–28 July, Cambridge, A12 (abstract)

  • Mueller EA, Murphy EA, Sunderland T (1985) Neuroendocrine effects ofm-chlorophenylpiperazine, a serotonin agonist, in humans. J Clin Endocrinol Metab 61:1–6

    Google Scholar 

  • Murphy DL, Brooks A, Aulakh C, Pigott TA (1993) Anxiolytic effects of drugs acting on 5-HT receptor subtypes. In: Vanhoutte PM, Saxena PR, Paoletti R, Brunello N, Jackson AS (eds) Serotonin — from cell biology to pharmacology and therapeutics. Kluwer Academic Publishers, Boston, pp 223–230

    Google Scholar 

  • Nutt DJ, Glue P (1991) Imipramine in panic disorder: I. Clinical response and pharmacological changes. J Psychopharmacol 5:56–64

    Google Scholar 

  • Onaivi ES, Martin BR (1989) Neuropharmacological and physiological validation of a computer-controlled two-compartment black and white box for the assessment of anxiety. Prog Neuropsychopharmacol Biol Psychiatry 13:963–976

    Google Scholar 

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

    Google Scholar 

  • Rutter JJ, Auerbach SB (1993) Acute uptake inhibition increases extracellular serotonin in the rat forebrain. J Pharmacol Exp Ther 265:1319–1324

    Google Scholar 

  • Saletu B, Grünberger J (1985) Classification and determination of cerebral bioavailability of fluoxetine: pharmacokinetic, pharmaco-EEG and psychometric analyses. Clin Psychiatry 46:45–52

    Google Scholar 

  • Sanger DJ (1990) Effects of buspirone and related compounds on suppressed operant responding in rats. J Pharmacol Exp Ther 254:420–426

    Google Scholar 

  • Sanger DJ (1992) Increased rates of punished responding produced by buspirone-like compounds in rats. J Pharmacol Exp Ther 261:513–517

    Google Scholar 

  • Schneier FR, Liebowitz MR, Davies SO, Fairbanks J, Hollander E, Campeas R, Klein DF (1990) Fluoxetine in panic disorder. J Clin Psychopharmacol 10:119–121

    Google Scholar 

  • Schütz MTB, de Aguiar JC, Graeff FG (1985) Anti-aversive role of serotonin in the dorsal periaqueductal grey matter. Psychopharmacology 85:340–345

    Google Scholar 

  • Treit D (1991) Anxiolytic effects of benzodiazepines and 5-HT1A agonists: animal models. In: Rodgers RJ, Cooper SJ (eds) 5-HT1A agonists, 5-HT3 antagonists and benzodiazepines: their comparative behavioural pharmacology. Wiley, Chichester, pp 107–131

    Google Scholar 

  • Van Praag HM (1988) Serotonin disturbances in psychiatric disorders: functional versus nosological interpretation. Adv Biol Psychiatry 17:52–57

    Google Scholar 

  • Westenberg HGM, Den Boer JA (1988) Clinical and biochemical effects of selective serotonin-uptake inhibitors in anxiety disorders. Adv Biol Psychiatry 17:84–99

    Google Scholar 

  • Westenberg HGM, Den Boer JA (1993) Serotonin and related disorders. In: Vanhoutte PM, Saxena PR, Paoletti R, Brunello N, Jackson AS (eds) Serotonin — from cell biology to pharmacology and therapeutics. Kluwer Academic Publishers, Boston, pp 249–254

    Google Scholar 

  • Young R, Johnson DN (1991) A fully automated light/dark apparatus useful for comparing anxiolytic agents. Pharmacol Biochem Behav 40:739–743

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Békésy Laboratory of Neurobiology, John A. Burns School of Medicine, University of Hawaii, 1993 East-West Road, 96822, Honolulu, HI, USA

    G. Griebel, D. C. Blanchard, R. S. Agnes & R. J. Blanchard

  2. Department of Anatomy and Reproductive Biology, John A. Burns School of Medicine, University of Hawaii, 1993 East-West Road, 96822, Honolulu, HI, USA

    D. C. Blanchard

  3. Department of Psychology, John A. Burns School of Medicine, University of Hawaii, 1993 East-West Road, 96822, Honolulu, HI, USA

    R. J. Blanchard

  4. CNS Pharmacology Group, Synthelabo Recherche (L.E.R.S.) 31, Avenue Paul-Vaillant Couturier, F-92220, Bagneux, France

    G. Griebel

Authors
  1. G. Griebel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. C. Blanchard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. S. Agnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. J. Blanchard
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Griebel, G., Blanchard, D.C., Agnes, R.S. et al. Differential modulation of antipredator defensive behavior in Swiss-Webster mice following acute or chronic administration of imipramine and fluoxetine. Psychopharmacology 120, 57–66 (1995). https://doi.org/10.1007/BF02246145

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02246145

Key words

Search

Navigation