Skip to main content
SpringerLink
Log in

Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs

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

Abstract

Rats may produce ultrasonic vocalizations (USV) in threatening situations. USV of adult male rats in association with aversive stimulation was evaluated as a screening method for anxiolytic drugs. The triazolobenzodiazepine alprazolam, the 5-HT uptake inhibitors fluvoxamine and clomipramine, the mixed 5-HT/NA uptake inhibitor imipramine, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378, theα 2-adrenoceptor agonist clonidine and theα 2-adrenoceptor antagonist yohimbine reduced conditioned USV. The classical benzodiazepines (BZD) diazepam and chlordiazepoxide were ineffective or had a very low potency to decrease USV. The partial BZD receptor agonists bretazenil, alpidem and zolpidem, the BZD receptor antagonist flumazenil, the NA uptake inhibitors desipramine and maprotiline, and the 5-HT3 receptor antagonist ondansetron had no effect on conditioned USV. The dopamine-D2 receptor antagonist haloperidol reduced USV at a very high dose. In separate experiments the effects of these drugs on locomotor activity were assessed. There was, however, no direct relationship between effects on motor behaviour and USV. In conclusion, the sensitivity of conditioned USV to 5-HT uptake inhibitors and alprazolam versus the insensitivity to classical benzodiazepines and NA uptake inhibitors provides a very interesting profile, which closely resembles the psychopharmacology of panic disorder. Also the face validity of conditioned USV towards situational panic attacks is high. We therefore propose conditioned USV in adult male rats as a novel behavioural paradigm to screen for anti-panic drugs.

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.

Similar content being viewed by others

References

  • Ballenger JC, Burrows GD, DuPont RL Jr Lesser IM, Noyes R Jr, Pecknold JC, Rifkin A, Swinson RP (1988) Alprazolam in panic disorder and agoraphobia: results from a multicentre trial. I. Efficacy in short-term treatment. Arch Gen Psychiatry 45:413–422

    PubMed  Google Scholar 

  • Beardslee SL, Papadakis E, Fontana DJ, Commissaris RL (1990) Antipanic drug treatments: failure to exhibit anxiolytic-like effects on defensive burying behaviour. Pharmacol Biochem Behav 35:451–455

    Article  PubMed  Google Scholar 

  • Blanchard RJ, Blanchard DC, Agullana R, Weiss SM (1991) Twenty-two kHz alarm cries to presentation of a predator, by laboratory rats living in visible burrow systems. Physiol Behav 50:967–972

    Google Scholar 

  • Broekkamp CL, Dortmans C, Berendsen HHG, Jenck F (1991) Pharmacology of fear, induced by periaqueductal grey stimulation in the rat. In: Olivier B, Mos J, Slangen JL (eds) Animal models in psychopharmacology. Birkhäuser, Basel, pp 69–74

    Google Scholar 

  • Cassano GB, Petracca A, Perugi G, Nisita C, Musetti L, Mengali F, McNair DM (1988) Clomipramine for panic disorder. I. The first 10 weeks of a long-term comparison with imipramine. J Affect Disord 14:123–127

    Article  PubMed  Google Scholar 

  • Charney DS, Heninger GR, Breier A (1984) Noradrenergic functioning in panic anxiety: effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 41:751–763

    PubMed  Google Scholar 

  • Chouinard G, Annable L, Fontaine R, Solyon L (1982) Alprazolam in the treatment of generalized anxiety and panic disorders: a double-blind, placebo-controlled study. Psychopharmacology 77:229–233

    Article  PubMed  Google Scholar 

  • Commissaris RL, Fontana DJ (1991) A potential animal model for the study of anti-panic treatments. In: Olivier B, Mos J, Slangen JL (eds) Animal models in psychopharmacology. Birkhäuser, Basel, pp 59–64

    Google Scholar 

  • 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 32:777–785

    Article  PubMed  Google Scholar 

  • Cuomo V, Cagiano R, De Salvia MA, Maselli MA, Renna G, Racagni G (1988) Ultrasonic vocalization in response to unavoidable aversive stimuli in rats: effects of benzodiazepines. Life Sci 43:485–491

    Article  PubMed  Google Scholar 

  • Den Boer JA, Westenberg HGM, Kamerbeek WDJ, Verhoeven WMA, Kahn RS (1987) Effect of serotonin uptake inhibitors in anxiety disorders: a double-blind comparison of clomipramine and fluvoxamine. Int Clin Psychopharmacol 2:21–32

    PubMed  Google Scholar 

  • De Vry J, Benz U, Schreiber R, Traber J (1993) Shock-induced ultrasonic vocalization in young adult rats: a model for testing putative anti-anxiety drugs. Eur J Pharmacol 249:331–339

    Article  PubMed  Google Scholar 

  • Dunner DL, Ishiki D, Avery DH, Wilson LG, Hyde TS (1986) Effect of alprazolam and diazepam on anxiety and panic attacks in panic disorder: a controlled study. J Clin Psychiatry 47:458–560

    PubMed  Google Scholar 

  • File SE, Pellow S (1985) The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard. Br J Pharmacol 86:729–735

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Gardner CR (1985) Distress vocalization in rat pups. A simple screening method for anxiolytic drugs. J Pharmacol Methods 14:181–187

    Article  PubMed  Google Scholar 

  • Goa KL, Ward A (1986) Buspirone: A preliminary review of its pharmacological properties and therapeutic efficacy as an anxiolytic. Drugs 32:114–129

    PubMed  Google Scholar 

  • Hjörth S, Carlsson A, Lindberg P, Sanches D, Wikström H, Arvidsson L-E, Hacksell U, Nilsson JLG (1982) 8-Hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, a potent and selective simplified ergot congener with central 5-HT-receptor stimulating activity. J Neural Transm 55:169–188

    Article  Google Scholar 

  • Hofer MA, Shair HN (1987) Isolation distress in two-week old rats: influence of home cage, social companions, and prior experience with littermates. Dev Psychobiol 20:565–476

    Article  Google Scholar 

  • Insel TR, Hill JL, Mayor RB (1986) Rat pup isolation calls: possible mediation by the benzodiazepine receptor complex. Pharmacol Biochem Behav 24:1263–1267

    Google Scholar 

  • Johnston AL, File SE (1988) Profiles of the antipanic compounds, triazolobenzodiazepines and phenelzine, in two animal tests of anxiety. Psychiatry Res 25:81–90

    PubMed  Google Scholar 

  • Kaltwasser MT (1991) Acoustic startle induced ultrasonic vocalizations in the rats: a novel animal model of anxiety? Behav Brain Res 43:133–137

    PubMed  Google Scholar 

  • Kalus O, Asnis GM, Rubinson E, Kahn R, Harkavy-Friedman JM, Iqbal N, Grosz D, Van Praag H, Cahn W (1991) Desipramine treatment in panic disorder. J Affect Disord 21:239–244

    Article  PubMed  Google Scholar 

  • Klerman GL (1992) Treatments for panic disorder. J Clin Psychiatry 53:14–19

    Google Scholar 

  • Ko GN, Elsworth JD, Roth RH, Rifkin BG, Leigh H, Redmond DE (1983) Panic-induced elevations of plasma MHPG levels in phobic-anxious patients: effects of clonidine and imipramine. Arch Gen Psychiatry 40:425–450

    PubMed  Google Scholar 

  • Langer SZ, Arbilla S, Tan S, Lloyd KG, George P, Allen J, Wick AE (1990) Selectivity for omega-receptor subtypes as a strategy for the development of anxiolytic drugs. Pharmacopsychiatry 23:103–107

    PubMed  Google Scholar 

  • Lesch KP, Wiesman M, Hoh A, Mueller T, Disselkamp-Tietze J, Osterheider M, Schulte HM (1982) 5-HT1A receptor-effector system responsivity in panic disorder. Psychopharmacology 106:111–117

    Google Scholar 

  • Lydiard RB (1987) Desipramine in agoraphobia with panic attacks: an open, fixed dose study. J Clin Psychopharmacol 7:258–260

    PubMed  Google Scholar 

  • Martin KF, Mason R (1987) Ipsapirone is a partial agonist at 5-hydroxytryptamine1A receptors in the rat hippocampus: electrophysiological evidence. Eur J Pharmacol 141:479–484

    Article  PubMed  Google Scholar 

  • Mavissakalian M, Michelson L (1986) Agoraphobia: relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine. J Clin Psychiatry 47:117–122

    PubMed  Google Scholar 

  • McNair DM, Kahn RJ (1981): Imipramine compared with a benzodiazepine for agoraphobia. In: Klein DF, Rabkin J (eds) Anxiety: new research and changing concepts, Raven Press, New York, pp 69–80

    Google Scholar 

  • McTavish, Benfield P (1990) Clomipramine: an overview of its pharmacological properties and a review of its therapeutic use in obsessive compulsive disorder and panic disorder. Drugs 39:136–153

    PubMed  Google Scholar 

  • Miczek KA, Vivian JA (1993) Automated quantification of withdrawal from 5-day diazepam in rats: ultrasonic distress vocalizations and hyperreflexia to acoustic startle stimuli. Psychopharmacology 110:379–382

    PubMed  Google Scholar 

  • Miczek KA, Tornatzky W, Vivian J (1991) Ethology and neuropharmacology: rodent ultrasounds. In: Olivier B, Mos J, Slangen JL (eds) Animal models in psychopharmacology. Birkhäuser, Basel, pp 409–427

    Google Scholar 

  • Mos J, Olivier B (1989) Ultrasonic vocalizations by rat pups as an animal model for anxiolytic activity: effects of serotonergic drugs. In: Bevan P, Cools AR, Archer T (eds) Behavioural pharmacology of 5-HT. Lawrence Erlbaum, New Jersey, pp 361–366

    Google Scholar 

  • Noyes R Jr, Anderson DJ, Clancy J, et al (1984) Diazepam and propranolol in panic disorder and agoraphobia. Arch Gen Psychiatry 41:287–292

    PubMed  Google Scholar 

  • Nutt DJ, Glue P, Lawson C, Wilson S (1990) Flumazenil provocation of panic attacks. Evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry 47:917–925

    PubMed  Google Scholar 

  • Perel JM, Foglia JP, Mavissakalian M, Lin FC, Narayan S (1988) Monitoring of imipramine (IMI) and desipramine (DMI) in patients with panic and phobic disorders. Clin Chem 34:1262

    Google Scholar 

  • Rifkin A, Klein DF, Dillon D, Levitt M (1981) Blockade by imipramine or desipramine of panic induced by sodium lactate. Am J Psychiatry 138:676–677

    PubMed  Google Scholar 

  • Robinson DS, Shrotriya RC, Alms DR, Messina M, Andary J (1989) Treatment of panic disorder: nonbenzodiazepine anxiolytics including buspirone. Psychopharmacol Bull 25:21–26

    PubMed  Google Scholar 

  • Sanchez C (1993) Effect of serotonergic drugs on footshock-induced ultrasonic vocalization in adult male rats. Behav Pharmacol 4:269–277

    PubMed  Google Scholar 

  • Sanger DJ, Joly D, Zivkovic B (1985) Behavioral effects of non-benzodiazepine anxiolytic drugs: a comparison of CGS 9896 and zopiclone with chlordiazepoxide. J Pharmacol Exp Ther 232:831–837

    PubMed  Google Scholar 

  • Sanger DJ, Perrault G, Morel E, Joly D, Zivkovic B (1987) The behavioural profile of zolpidem, a novel hypnotic drug of imidazopyridine structure. Physiol Behav 41:235–240

    Google Scholar 

  • Schneier FR, Carrasco JL, Hollander E, Campeas R, Fallon B, Saoud JB, Feerick JB, Liebowitz MR (1993) Alpidem in the treatment of panic disorder. J Clin Psychopharmacol 13:150–153

    PubMed  Google Scholar 

  • Schuurman T, Benz U (1990) Verhaltenspharmakologie — ein integrativer Teil der ZNS-Forschung. In: Glaser T, Heinrich K (eds) Psychopharmaka-forschung aktuell. Schattauer, Stuttgart, pp 177–192

    Google Scholar 

  • Sheehan DV (1982) Current views in the treatment of panic and phobic disorders. Drug Ther Hosp 7:74–93

    Google Scholar 

  • Sheehan DV, Raj AB, Sheehan KH, Soto S (1990) Is buspirone effective for panic disorder? J Clin Psychopharmacol 10:3–11

    PubMed  Google Scholar 

  • Sheehan DV, Raj AB, Harnett Sheehan K, Soto S, Knapp E (1993) The relative efficacy of high-dose buspirone and alprazolam in the treatment of panic disorder: a double-blind placebo-controlled study. Acta Psychiatr Scand 88:1–11

    PubMed  Google Scholar 

  • Söderpalm B, Eriksson E, Engel JA (1989) Anticonflict and rotarod impairing effects of alprazolam and diazepam in rat after acute and subchronic administration. Prog Neuropsychopharmacol Biol Psychiatry 13:269–283

    Article  PubMed  Google Scholar 

  • Swinson RP, Kuch K (1990) Clinical features of panic and related disorders. In: Ballenger JC (ed) Clinical aspects of panic disorder. Wiley-Liss, New York, pp 13–30

    Google Scholar 

  • Tonoue T, Ashida Y, Makino H, Hata H (1986) Inhibition of shock-elicited ultrasonic vocalization by opioid peptides in the rat: a psychotropic effect. Psychoneuroendocrinology 11:177–184

    Article  PubMed  Google Scholar 

  • Tornatzky W, Miczek KA (1992) Behaviour and telemetered autonomic responses to alcohol and social stress. Soc Neurosci Abstr 18:715

    Google Scholar 

  • Uhde TW, Stein MB, Vittone BJ, Siever LJ, Boulenger JP, Klein E (1989) Behavioural and physiological effects of short-term and long-term administration of clonidine in panic disorder. Arch Gen Psychiatry 56:170–177

    Google Scholar 

  • Van der Poel AM, Miczek KA (1991) Long ultrasonic calls in male rats following mating, defeat and aversive stimulation: frequency modulation and bout structure. Behaviour 119:127–142

    Google Scholar 

  • Van der Poel AM, Noach EJK, Miczek KA (1989) Temporal pattern of ultrasonic distress calls in the adult rat: effects of morphine and benzodiazepines. Psychopharmacology 97:147–148

    Article  PubMed  Google Scholar 

  • Vivian JA, Miczek KA (1993) Diazepam and gepirone selectively attenuate either 20–32 or 32–64 kHz ultrasonic vocalizations during aggressive encounters. Psychopharmacology 112:66–73

    Article  PubMed  Google Scholar 

  • Vivian JA, Farrell WJ, Sapperstein SB, Miczek KA (1994) Diazepam withdrawal: effects of diazepam and gepirone on acoustic startle-induced 22 kHz ultrasonic vocalizations. Psychopharmacology 114:101–108

    PubMed  Google Scholar 

  • Wamsley JK, Longlet LL, Hunt ME, Mahan DR, Alburges ME (1993) Characterization of the binding and comparison of the distribution of benzodiazepine receptors labeled with [3H]diazepam and [3H]alprazolam. Neuropsychopharmacology 8:305–314

    PubMed  Google Scholar 

  • Westenberg HGM, Den Boer JA (1989) Selective monoamine uptake inhibitors and a serotonin antagonist in the treatment of panic disorder. Psychopharmacol Bull 25:119–123

    PubMed  Google Scholar 

  • Westenberg HGM, Den Boer JA (1990) Guidelines to ensure antipanic drugs are effective. Clin Neuropharmacol 13:655–656

    Google Scholar 

  • Winter JC, Rabin R (1992) Yohimbine as a serotonergic agent: evidence from receptor binding and drug discrimination. J Pharmacol Exp Ther 263:682–689

    PubMed  Google Scholar 

  • Woods SW, Charney DS, Silver JM, Krystal JH, Heninger GR (1991) Behavioural, biochemical and cardiovascular responses to the benzodiazepine receptor antagonist flumazenil in panic disorder. Psychiatry Res 36:155–127

    Article  Google Scholar 

  • Wouters W, Hartog J, Bevan P (1988) Flesinoxan. Drug Dev Rev 6:71–83

    Google Scholar 

  • Ybema CE, Slangen JL, Olivier B, Mos J (1993) Dose-dependent discriminative stimulus properties of 8-OH-DPAT. Behav Pharmacol 4:610–624

    PubMed  Google Scholar 

  • Yocca FD, Hyslop DK, Smith DW, Maayani S (1887) BMY 7378, a buspirone analogue with high affinity, selectivity and low intrinsic activity at the 5-HT1A receptor in rat and guinea pig hippocampal membranes. Eur J Pharmacol 137:293–294

    Article  Google Scholar 

  • Zitrin CM, Klein DF, Woerner MG (1880) Treatment of agoraphobia with group exposure in vivo and imipramine. Arch Gen Psychiatry 37:63–72

    Google Scholar 

  • Zivkovic B, Morel E, Joly D, Perrault G, Sanger DJ, Lloyd KG (1990) Pharmacological and behavioural profile of alpidem as an anxiolytic. Pharmacopsychiatry [Suppl] 23:108–113

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CNS Pharmacology, Solvay Duphar B.V., PO Box 900, 1380 DA, Weesp, The Netherlands

    H. E. Molewijk, A. M. van der Poel, J. Mos, J. A. M. van der Heyden & B. Olivier

  2. Department of Psychopharmacology, Faculty of Pharmacy, Utrecht University, Sorbonnelaan 16, 3584 CA, Utrecht, The Netherlands

    B. Olivier

Authors
  1. H. E. Molewijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. M. van der Poel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Mos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. A. M. van der Heyden
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B. Olivier
    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

Molewijk, H.E., van der Poel, A.M., Mos, J. et al. Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening anti-panic drugs. Psychopharmacology 117, 32–40 (1995). https://doi.org/10.1007/BF02245095

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02245095

Key words

Search

Navigation