Psychopharmacology

, Volume 114, Issue 1, pp 101–108 | Cite as

Diazepam withdrawal: effects of diazepam and gepirone on acoustic startle-induced 22 kHz ultrasonic vocalizations

  • Jeffrey A. Vivian
  • William J. Farrell
  • Scott B. Sapperstein
  • Klaus A. Miczek
Original Investigations

Abstract

It has proven difficult to demonstrate and study the “anxiogenic” quality of drug withdrawal states in animals. Ultrasonic vocalizations (USV) in response to acoustic startle stimuli have shown promise as a measure of affect and may represent “distress” responses during diazepam withdrawal. Three experiments evaluated the association between USV and “distress” by comparing the effects of diazepam as a prototypic benzodiazepine agonist and the putative anxiolytic gepirone with affinity for 5-hydroxytryptamine (5-HT1A) receptors in naive and diazepam-withdrawn subjects. Adult male Long-Evans rats were exposed to acoustic startle sessions consisting of nine 105 dB and nine 115 dB stimuli. USV at 20–30 kHz were readily emitted during startle and often commenced after the third or fourth stimulus presentation. Acutely, intraperitoneal (IP) administration of diazepam (0.1–3 mg/kg) and gepirone (0.1–1 mg/kg) decreased USV dose-dependently without affecting the startle reflex; gepirone also decreased tail flick latency. Startle-induced USV were also sensitive to the “anxiogenic” effects of withdrawal from diazepam exposure (0, 2.5, 5, 10 mg/kg b.i.d. IP×5 days). Twenty-four hours after the last diazepam injection, rats were hyperreactive to startle stimuli and doubled their rate of USV over vehicle-treated controls. Gepirone (0.1–1 mg/kg IP), but not diazepam (3–20 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 10 mg/kg b.i.d. diazepam. Diazepam (2.5–10 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 2.5 mg/kg b.i.d. diazepam. USV induced by acoustic startle stimuli are sensitive to the anxiolytic effects of benzodiazepine and 5-HT1A receptor agonists and permit the assessment of the “anxiogenic” properties of diazepam withdrawal. The potent effect of gepirone on USV suggests a serotonergic amelioration of the “anxiogenic” aspects of diazepam withdrawal.

Key words

Acoustic startle Affect Analgesia Anxiolytics Diazepam Gepirone Thermoregulation Ultrasonic vocalization Withdrawal 

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References

  1. Andrews N, File SE (1992) Are there changes in sensitivity to 5-HT3 receptor ligands following chronic diazepam treatment? Psychopharmacology 108:333–337Google Scholar
  2. Barfield RJ, Geyer LA (1972) Sexual behavior: ultrasonic postejaculatory song of the male rat. Science 176:1349–1350Google Scholar
  3. Barrett JE (1991) Animal behaviour models in the analysis and understanding of anxiolytic drugs acting at serotonin receptors. In: Olivier B, Mos J, Slangen JL (eds) Animal models in psychopharmacology. Birkhauser Verlag, Basel, pp 37–52Google Scholar
  4. Barrett JE, Vanover KE (1993) 5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions. Psychopharmacology 112:1–12Google Scholar
  5. Berge OG, Post C, Archer T (1989) The behavioral pharmacology of serotonin in pain processes. In: Bevans P, Cools A, Archer T (eds) Behavioural Pharmacology of 5-HT. Lawrence Erlbaum, Hillsdale, pp 301–319Google Scholar
  6. Copland AM, Balfour DJK (1987) The effects of diazepam on brain 5-HT and 5-HIAA in stressed and unstressed rats. Pharmacol Biochem Behav 27:619–624Google Scholar
  7. Costall B, Jones BJ, Kelly ME, Naylor RJ, Oakley NE, Onaivi ES, Tyers MB (1989) The effects of ondansetron (GRF38032F) in rats and mice treated subchronically with diazepam. Pharmacol Biochem Behav 34:769–778Google Scholar
  8. Costall B, Jones BJ, Kelly ME, Naylor RJ, Onaivi ES, Tyers MB (1990) Sites of action of ondansetron to inhibit withdrawal from drugs of abuse. Pharmacol Biochem Behav 36:97–104Google Scholar
  9. Cuomo V, Cagiano R, DeSalvia MA, Maselli MA, Renna G, Racagni G (1988) Ultrasonic vocalization in response to unavoidable aversive stimuli in rats: effects of benzodiazepines. Life Sci 43:485–491Google Scholar
  10. D'Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79Google Scholar
  11. Dewey WL, Harris LS (1975) The tail flick test. In: Ehrenpreis S, Neidle A (eds) Methods in narcotics research. Dekker, New York, pp 101–109Google Scholar
  12. Eison AS, Eison ES, Stanley M, Riblet, LA (1986) Serotonergic mechanisms in the behavioral effects of buspirone and gepirone. Pharmacol Biochem Behav 24:701–707Google Scholar
  13. File SE (1990) The history of benzodiazepine dependence: A review of animal studies. Neurosci Biobehav Rev 14:135–146Google Scholar
  14. File SE, Andrews N (1991) Low but not high doses of buspirone reduce the anxiogenic effects of diazepam withdrawal. Psychopharmacology 105:578–582Google Scholar
  15. File SE, Mabbutt PS, Andrews N (1991) Diazepam withdrawal responses measured in the social interaction test of anxiety and their reversal by baclofen. Psychopharmacology 104:62–66Google Scholar
  16. Gardner CR (1985) Distress vocalizations in rat pups. A simple screening method for anxiolytic drugs. J Pharmacol Methods 14:181–187Google Scholar
  17. Goudie AJ, Leathley MJ (1991a) Evaluation of the dependence potential of the selective 5-HT1A agonist ipsapirone in rats and of its effects on benzodiazepine withdrawal. Psychopharmacology 103:529–537Google Scholar
  18. Goudie AJ, Leathley MJ (1991b) Effects of the 5-HT1A agonist anxiolytic gepirone on benzodiazepine withdrawal signs in rats. Behav Pharmacol 2:461–469Google Scholar
  19. Haney M, Miczek KA (1993) Ultrasounds during agonistic interactions between female rats (Rattus norvegicus). J Comp Psychol 107:373–379Google Scholar
  20. Hard E, Engel J (1988) Effects of 8-OH-DPAT on ultrasonic vocalization and audiogenic immobility reaction in pre-weanling rats. Neuropharmacology 27[10]:981–986Google Scholar
  21. Insel TR, Winslow JR (1991) Rat pup ultrasonic vocalizations: an ethologically relevant behaviour responsive to anxiolytics. In: Olivier B, Mos J, Slangen JL (eds) Animal models in psychopharmacology. Birkhauser, Basel, pp 15–36Google Scholar
  22. Insel TR, Hill JL, Mayor RB (1986) Rat pup ultrasonic isolation calls: possible mediation by the benzodiazepine receptor complex. Pharmacol Biochem Behav 24:1263–1267Google Scholar
  23. Insel TR, Gelhard RE, Miller LP (1989) Rat pup isolation distress and the brain benzodiazepine receptor. Dev Psychobiol 22:509–525Google Scholar
  24. Kachigan SK (1986) Statistical analysis. Radius, New YorkGoogle Scholar
  25. Kaltwasser MT (1990) Startle-inducing acoustic stimuli evoke ultrasonic vocalization in the rat. Physiol Behav 48:13–17Google Scholar
  26. Kaltwasser MT (1991) Acoustic startle induced ultrasonic vocalization in the rat: a novel animal model of anxiety? Behav Brain Res 43:133–137Google Scholar
  27. Killam EK, Matsuzaki M, Killam KF (1973) Effects of chronic administration of benzodiazepines on epileptic seizures and brain electrical activity inPapio papio. In: Garattini S, Mussini E, Randall LO (eds) The benzodiazepines. Raven, New York, pp 443–460Google Scholar
  28. Lader M, Petursson H (1983) Abuse liability of anxiolytics. In: Malick JB, Enna SJ, Yamamura HI (eds) Anxiolytics: neurochemical, behavioral, and clinical perspectives. Raven, New York, pp 201–214Google Scholar
  29. Leathley MJ, Goudie AJ (1992) Effects of the 5-HT3 antagonist ICS 205–930 on benzodiazepine withdrawal signs in rats. Behav Pharmacol 3:51–56Google Scholar
  30. Lukas SE, Griffiths RR (1982a) Precipitated withdrawal in diazepam-treated baboons by a benzodiazepine receptor antagonist. Fed Proc 41:1542Google Scholar
  31. Lukas SE, Griffiths RR (1982b) Precipitated withdrawal by a benzodiazepine receptor antagonist (Ro 15–1788) after 7 days of diazepam. Science 217:1161–1163Google Scholar
  32. Lukas SE, Griffiths RR (1984) Precipitated diazepam withdrawal in baboons: effects of dose and duration of diazepam exposure. Eur J Pharmacol 100:163–171Google Scholar
  33. Martin WR, McNicholas LF, Cherian S (1982) Diazepam and pentobarbital dependence in the rat. Life Sci 31:721–730Google Scholar
  34. McMillan DE, Leander JD (1978) Chronic chlordiazepoxide and pentobarbital interactions on punished and unpunished behavior. J Pharmacol Exp Ther 207:515–520Google Scholar
  35. McNicholas LF, Martin WR (1982) The effect of a benzodiazepine antagonist, RO15-1788, in diazepam dependent rats. Life Sci 31:731–737Google Scholar
  36. Miczek KA, Vivian JA (1993) Automatic quantification of withdrawal from 5-day diazepam in rats: ultrasonic distress vocalizations and hyperreflexia to acoustic startle stimuli. Psychopharmacology 110:379–382Google Scholar
  37. Miczek KA, Tornatzky W, Vivian JA (1991) Ethology and neuropharmacology: rodent ultrasounds. In: Oliver B, Mos J, Slangen JL (eds) Animal models in psychopharmacology. Birkhauser, Basel, pp 409–427Google Scholar
  38. Mos J, Van Logten J, Bloetjes K, Olivier B (1991) The effects of idazoxan and 8-OH-DPAT on sexual behaviour and associated ultrasonic vocalizations in the rat. Neurosci Biobehav Rev 15:505–510Google Scholar
  39. Przegalinski E, Tatarczynskz E, Chocjnacka-Wojcik E (1989) Anticonflict effect of ipsapirone, buspirone and gepirone is not mediated by their common metabolite 1-(2-pyrimidinyl)priperazine. J Psychopharmacol 3:180–185Google Scholar
  40. Sanchez C (1993) Effect of serotonergic drugs on footshock-induced ultrasonic vocalization in adult male rats. Behav Pharmacol 4:269–277Google Scholar
  41. Sanger DJ, Perrault G, Morel E, Joly D, Zivkovic B (1991) Animal models and recent developments in the search for novel anxiolytics. In: Olivier B, Mos J, Slangen JL (eds) Animal models in psychopharmacology. Birkhauser, Basel, pp 3–13Google Scholar
  42. Schreiber R, de Vry J (1993) 5-HT1A receptor ligands in animal models of anxiety, impulsivity and depression: multiple mechanisms of action? Prog Neuropsychopharmacol Biol Psychiatry 17:87–104Google Scholar
  43. Shepherd JK, Blanchard DC, Weiss SM, Rodgers RJ, Blanchard RJ (1992) Morphine attenuates antipredator ultrasonic vocalizations in mixed-sex rat colonies. Pharmacol Biochem Behav 41:551–558Google Scholar
  44. Tonoue T, Iwasawa H, Naito H (1986) Inhibition of shock elicited ultrasonic vocalization by opioid peptides in the rat: a psychotropic effect. Psychoneuroendocrinology 11:177–184Google Scholar
  45. Tornatzky W, Miczek KA (1990) Behavior and telemetered autonomic responses to clonidine, diazepam and social stress. Neurosci Abstr 16[1]:432Google Scholar
  46. Van der Poel AM, Noach EJK, Miczek KA (1989) Temporal patterning of ultrasonic distress calls in the adult rat: effects of morphine and benzodiazepines. Psychopharmacology 97:147–148Google Scholar
  47. Van der Poel AM, Miczek KA (1991) Long ultrasonic cells in male rats following mating, defeat and aversive stimulation: frequency modulation and bout structure. Behav 119:127–144Google Scholar
  48. Vivian JA, Miczek KA (1991) Ultrasounds during morphine withdrawal in rats. Psychopharmacology 104:187–193Google Scholar
  49. Vivian JA, Miczek KA (1993a) Morphine attenuates ultrasonic vocalizations during agonistic encounters in adult rats. Psychopharmacology 111:367–375Google Scholar
  50. Vivian JA, Miczek KA (1993b) Diazepam and gepirone selectively attenuate either 20 to 32 or 32 to 64-kHz ultrasonic vocalizations during aggressive encounters. Psychopharmacology 112:66–73Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Jeffrey A. Vivian
    • 1
  • William J. Farrell
    • 1
  • Scott B. Sapperstein
    • 1
  • Klaus A. Miczek
    • 1
  1. 1.Department of PsychologyTufts UniversityMedfordUSA

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