, Volume 101, Issue 4, pp 525–532 | Cite as

A theory of benzodiazepine dependence that can explain whether flumazenil will enhance or reverse the phenomena

  • Sandra E. File
  • Paul K. Hitchcott
Original Investigations


Repeated administration of benzodiazepines (BDZs) produces dependence in man and animals and this is reflected in the phenomena of tolerance and withdrawal responses. In BDZ-dependent animals the BDZ-receptor antagonist flumazenil (Ro 15-1788) reverses the increased anxiety and decreased seizure threshold seen when benzodiazepine treatment is withdrawn. In contrast are reports that flumazenil enhances BDZ-withdrawal responses. Indirect influences on the direction of flumazenil's effects on anxiety are the duration and dose of BDZ treatment, whether tolerance has developed to its anxiolytic effect and whether there is an anxiogenic response on drug withdrawal. However, we conclude that the crucial factor is the anxiety level of the animal: when this is high flumazenil becomes anxiolytic; when this is low flumazenil is anxiogenic. These bidirectional effects of flumazenil can be seen in drug-naive and BDZ-dependent animals. We propose a theory of benzodiazepine dependence that can account for anxiogenic responses on drug withdrawal and for flumazenil's bidirectional effects; central to this theory is the assumption that flumazenil normalises the benzodiazepine receptor, returning it to a baseline state. Thus it is whether an animal's score lies above or below this baseline that will determine the direction of flumazenil's effect. The clinical implications of this theory are discussed. We suggest that during the development of benzodiazepine dependence, two independent adaptive biochemical mechanisms are triggered: one underlying the development of tolerance to the anxiolytic responses, the other underlying the incidence of increased anxiety on drug withdrawal. It is only changes in the latter that are induced by the administration of flumazenil.

Key words

Benzodiazepine Withdrawal Tolerance Flumazenil Anxiety Seizures 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Baldwin HA, File SE (1988) Reversal of increased anxiety during benzodiazepine withdrawal: evidence for an anxiogenic endogenous ligand for the benzodiazepine receptor. Brain Res Bull 20:603–606Google Scholar
  2. Baldwin HA, File SE (1989) Flumazenil prevents the development of chlordiazepoxide withdrawal in rats tested in the social interaction test of anxiety. Psychopharmacology 97:424–426Google Scholar
  3. Baldwin HA, Hitchcott PK, File SE (1990) The use of flumazenil in prevention of diazepam dependence in the rat. Hum Psychopharmacol 5:57–61Google Scholar
  4. Emmett-Oglesby MW, Spencer D, Lewis M, Elmesallamy F, Lal H (1983) Anxiogenic aspects of diazepam withdrawal can be detected in animals. Eur J Pharmacol 92:127–130Google Scholar
  5. Emmett-Oglesby MW, Mathis DA, Lal H (1987) Diazepam tolerance and withdrawal assessed in an animal model of subjective drug effects. Drug Dev Res 11:145–156Google Scholar
  6. File SE (1984) Behavioural pharmacology of benzodiazepines. Prog Neuropsychopharm Biol Psychiatry 8:19–31Google Scholar
  7. File SE (1985) Tolerance to the behavioral actions of benzodiazepines. Neurosci Biobehav Rev 9:113–121Google Scholar
  8. File SE (1989) Chronic diazepam treatment: effect of dose on development of tolerance and incidence of withdrawal in an animal test of anxiety. Hum Psychopharmacol 4:59–63Google Scholar
  9. File SE (1990a) The history of benzodiazepine dependence: a review of animal studies. Neurosci Biobehav Rev 14:135–146Google Scholar
  10. File SE (1990b) One-trial tolerance to the anxiolytic effects of chlordiazepoxide in the plus-maze. Psychopharmacology 100:281–282Google Scholar
  11. File SE, Pellow S (1985a) Chlordiazepoxide enhances the anxiogenic action of CGS 8216 in the social interaction test: evidence for benzodiazepine withdrawal? Pharmacol Biochem Behav 23:33–36Google Scholar
  12. File SE, Pellow S (1985b) Does the benzodiazepine antagonist Ro 15-1788 reverse the actions of picrotoxin and pentylenetetrazole on social and exploratory behaviour? Arch Int Pharmacodyn Ther 277:272–279Google Scholar
  13. File SE, Pellow S (1986) Intrinsic actions of the benzodiazepine receptor antagonist, Ro 15-1788. Psychopharmacology 88:1–11Google Scholar
  14. File SE, Baldwin HA, Arnako K (1987) Anxiogenic effects from benzodiazepine withdrawal are linked to the development of tolerance. Brain Res Bull 19:607–610Google Scholar
  15. File SE, Baldwin HA, Hitchcott PK (1989) The effect of flumazenil on levels of anxiety in rats after one week of chronic diazepam treatment. Neurosci Lett S36:S63Google Scholar
  16. File SE, Mabbutt PS, Hitchcott PK (1990) Characterisation and explanation of the phenomenon of “one-trial tolerance” to the anxiolytic effect of chloridazepoxide. Psychopharmacology (in press)Google Scholar
  17. Gallager DW, Heninger K, Heninger G (1986) Periodic benzodiazepine administration prevents benzodiazepine withdrawal symptoms in primates. Eur J Pharmacol 132:31–38Google Scholar
  18. Gallaher EJ, Henauer SA, Jacques CJ, Hollister LE (1986) Benzodiazepine-dependence in mice after ingestion of drug containing food pellets. J Pharmacol Exp Ther 237:462–467Google Scholar
  19. Grant SJ, Galloway MP, Mayor R, Fenerty JP, Finkelstein MF, Roth RH, Redmond DE (1985) Precipitated diazepam withdrawal elevates noradrenergic metabolism in primate brain. Eur J Pharmacol 107:127–132Google Scholar
  20. Harris CM, Idemudia SO, Benjamin D, Bhadra S, Lal H (1988) Withdrawal from ingested diazepam produces a pentylenetetrazol-like stimulus in rats. Drug Dev Res 12:71–76Google Scholar
  21. Hitchcott PK, File SE, Little HJ, Nutt DJ (1989) Diazepam withdrawal: decreased seizure threshold and increased anxiety reversed by FG 7142 and flumazenil. Soc Neurosci Abstr 15:414Google Scholar
  22. Hitchcott PK, File SE, Ekwuru M, Neal MJ (1990) Chronic diazepam treatment in rats causes long-lasting changes in central [3H]-5-hydroxytryptamine and [14C]-γ-aminobutyric acid release. Br J Pharmacol 99:11–12Google Scholar
  23. Idemudia SO, Lal H (1989) Pentylenetetrazole-like stimulus is produced in rats during withdrawal from ingested chlordiazepoxide. Drug Dev Res 16:23–29Google Scholar
  24. Kunchandy J, Kulkarni SK (1986) Reversal by alpha-2 agonists of diazepam hyperactivity in rats. Psychopharmacology 90:198–202Google Scholar
  25. Lader MH, File SE (1987) The biological basis of benzodiazepine dependence. Psychol Med 17:539–547Google Scholar
  26. Lamb RJ, Griffiths RR (1984) Precipitated and spontaneous withdrawal in baboons after chronic dosing with lorazepam and CGS 9896. Drug Alcohol Depend 14:11–17Google Scholar
  27. Lamb RJ, Griffiths RR (1985) Effects of repeated Ro 15-1788 administration in benzodiazepine-dependent baboons. Eur J Pharmacol 110:257–261Google Scholar
  28. Little HJ, Nutt DJ, Taylor SC (1986) Does chronic benzodiazepine administration cause a “withdrawal shift” across the whole benzodiazepine ligand spectrum? Br J Pharmacol 89:796PGoogle Scholar
  29. Little HJ, Nutt DJ, Taylor SC (1987) Bidirectional effects of chronic treatment with agonists and inverse agonists at the benzodiazepine receptor. Brain Res Bull 19:371–378Google Scholar
  30. Little HJ, Gale R, Sellars N, Nutt DJ, Taylor SC (1988) Chronic benzodiazepine treatment increases the effects of the inverse agonist FG 7142. Neuropharmacology 27:383–389Google Scholar
  31. Lukas SE, Griffiths RR (1982) 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. Marietta CA, Eckardt MJ, Zbicz KL, Weight FF (1984) Alterations in glucose uptake in brain in diazepam-dependent and diazepam-withdrawing rats. Soc Neurosci Abstr 10:1208Google Scholar
  34. McNicholas LF, Martin WR (1982) The effect of a benzodiazepine antagonist, RO 15-1788, in diazepam-dependent rats. Life Sci 31:731–737Google Scholar
  35. Miyata M, Mochetti I, Ferrarese C, Guidotti A, Costa E (1987) Protracted treatment with diazepam increases the turnover of putative endogenous ligands for the benzodiazepine/β-carboline recognition site. Proc Natl Acad Sci USA 84:1444–1448Google Scholar
  36. Nutt DJ, Costello MJ (1988) Rapid induction of lorazepam dependence and reversal with flumazenil. Life Sci 43:1045–1053Google Scholar
  37. Oakley NR, Jones BJ, Tyers MB (1988) Tolerance and withdrawal studies with diazepam and GR38032F in the rat. Br J Pharmacol 96:764PGoogle Scholar
  38. Oswald I, Priest RG (1965) Five weeks to escape the sleeping pill habit. Br Med J 2:1093–1099Google Scholar
  39. 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 14:149–167Google Scholar
  40. Petersen EN, Jensen LH (1987) Chronic treatment with lorazepam and FG 7142 may change the effects of benzodiazepine receptor agonists, antagonists and inverse agonists by different mechanisms. Eur J Pharmacol 133:309–317Google Scholar
  41. Ryan GP, Boisse NR (1983) Experimental induction of benzodiazepine tolerance and physical dependence. J Pharmacol Exp Ther 226:100–107Google Scholar
  42. Schatzki A, Lopez F, Greenblatt DJ, Shader RI, Miller LG (1989) Lorazepam discontinuation promotes “inverse agonist” effects of benzodiazepines. Br J Pharmacol 98:451–454Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • Sandra E. File
    • 1
  • Paul K. Hitchcott
    • 1
  1. 1.Psychopharmacology Research Unit, UMDS, Division of PharmacologyUniversity of London, Guy's HospitalLondonUK

Personalised recommendations