Skip to main content
Log in

Changes in noradrenaline plasma levels and behavioural responses induced by benzodiazepine agonists with the benzodiazepine antagonist Ro 15-1788

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

Abstract

Noradrenaline (NA) plasma levels were examined in 18 healthy volunteers on 2 consecutive days after a single treatment with either lormetazepam (0.06 mg/kg) (LMZ group), flunitrazepam (0.03 mg/kg) (FNZ group) or placebo (PLA group) in combination with the benzodiazepine (BZ) antagonist Ro 15-1788 (0.1 mg/kg). Behavioural responses (mood changes, anxiety) were also investigated in parallel. Both BZ decreased NA plasma levels to 50% of the basal values 10 min after the injection; administration of Ro 15-1788 15 min later reinstated NA plasma levels to basal values. A second administration of Ro 15-1788 (0.1 mg/kg) 24 h after BZ or PLA treatment increased NA plasma levels, estimated 10 min after the injection in both the LMZ- and the FNZ groups, but not in the PLA group. Behavioural responses measured under the same treatment also indicated minor anxiety responses followed by mood impairment. These data suggest that a stressful situation may be precipitated by the antagonist Ro 15-1788 24 h after a single BZ treatment, which resembles a withdrawal response, and increases NA plasma levels.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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

  • Ackenheil M, Fröhler M, Goldig G, Rall G, Welter D (1982) Katecholamin-Bestimmung im Blut und Liquor mit Hochdruckflüssigkeitschromatographie und elektrochemischem Detektor. Arzneim Forsch (Drug Res) 32:893

    Google Scholar 

  • Biggio G (1983) The action of stress, β-carbolines, diazepam and Ro 15–1788 on GABA receptors in the rat brain. In: Biggio G, Costa E, (eds) Advance in biochemical pharmacology. Raven Press, New York

    Google Scholar 

  • Braestrup C, Squires RF (1977) Specific benzodiazepine receptors in rat brain characterised by high-affinity (3H) diazepam binding. Proc Natl Acad Sci USA 74:3805–3804

    Google Scholar 

  • Charney DS, Redmond DE Jr, Galloway MP, Kleber HD, Henniger GR, Murberg M, Roth RH (1984) Naltrexone precipitated opiate withdrawal in methadone addicted human subjects: Evidence for noradrenergic hyperactivity. Life Sci 35:1263–1272

    Google Scholar 

  • Cooper JR, Bloom FE, Roth RH (1978) The biochemical basis for neuropharmacology. University Press, New York, pp 102–195

    Google Scholar 

  • Corrodi H, Fuxe K, Hökfelt T (1967) The effect of some psychoactive drugs on central monoamine neurons. Eur J Pharmacol 1:363–368

    Google Scholar 

  • Da Prada M, Pieri L, Picotti GB (1980) Effects of midazolam (a water soluble benzodiazepine) on stress-induced increase of plasma catecholamines. In: Usdin E, Kvetnansky R, Kopin IJ (eds) Catecholamines and stress: recent advances. Elsevier, Amsterdam, pp 231–236

    Google Scholar 

  • Darragh A, Lambe R, Scully M, Brick I, O'Boyle C, Downie WW (1981) Investigation in man of the efficacy of a benzodiazepine antagonist, Ro 15–1788. Lancet ii:8–10

    Google Scholar 

  • DeTurek K, Vogel WH (1982) Effects of acute ethanol on plasma and brain catecholamine levels in stressed and unstressed rats: Evidence for an ethanolstress interaction. J Pharm Expt Ther 223:348–354

    Google Scholar 

  • Dionne RA, Goldstein DS, Wirdzek PR (1984) Effects of diazepam premedication and epinephrine-containing local anesthetic on cardiovascular and plasma catecholamine responses to oral surgery. Anesth-Analg 63:640–646

    Google Scholar 

  • Dorow R, Seidler J, Schneider HH (1982) A radioreceptor assay to study the affinity of benzodiazepines and their receptor binding activity in human plasma including their active metabolites. Br J Clin Pharmacol 13:561–565

    Google Scholar 

  • Dorow R, Doenicke A, Suttmann H, Gräf K-J, Grote B, Bretz Ch, Sarafoff M, Ott H (1983) Einfluβ verschiedener Narkosemethoden auf hormonelle Parameter und auf das sympathonervale System In: Doenicke A, Koenig KD (eds) Immunologie in Anästhesie und Intensivmedizin. Springer Verlag, New York

    Google Scholar 

  • Elmadjian FJ, Hope M, Lamson ET (1957) Excretion of epinephrine and norepinephrine in various emotional states. J Clin Endocrinol 17:608–620

    Google Scholar 

  • Emmett-Oglesby M, Spencer DG Jr, Lewis MW, Elmesallamy F, Lal H (1983) Anxiogenic aspects of diazepam withdrawal can be detected in animals. Eur J Pharmacol 92:127–130

    Google Scholar 

  • File SE, Lister RG, Nutt DJ (1982) The anxiogenic action of benzodiazepine antagonists. Neuropharmacology 21:1033–1037

    Google Scholar 

  • Fontaine R, Chouinard G, Annable L (1984) Rebound anxiety in anxious patients after abrupt withdrawal of benzodiazepine treatment. Am J Psychiatry 141:848–852

    Google Scholar 

  • Frankenhaeuser M (1971) Behavior and circulating catecholamines. Brain Res 31:241–262

    Google Scholar 

  • Goldstein DS, Dionne R, Sweet J, Gracely R, Brewer HB Jr, Gregg R, Keiser HR (1982) Circulatory, plasma catecholamine, cortisol, lipid, and psychological responses to a real-life stress (third molar extractions): Effects of diazepam sedation and of inclusion of epinephrine with the local anesthetic. Psychosom Med 44:259–272

    CAS  PubMed  Google Scholar 

  • Goodman Gilman A, Goodman LS, Rall TW, Murad F (eds) (1985) The pharmacological basis of therapeutics, 7th edition. MacMillan Publishing Company, New York

    Google Scholar 

  • Hossmann V, Maling TJB, Hamilton CA, Reid JL, Dollery CT (1980) Sedative and cardiovascular effects of clonidine and nitrazepam. Clin Pharmacol Ther 28:167–176

    Google Scholar 

  • Hunkeler W, Mohler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290:514–516

    Google Scholar 

  • Kales A, Soldatos CR, Bixler EO, Kales JD (1983) Rebound insomnia and rebound anxiety: A review. Pharmacology 26:121–137

    Google Scholar 

  • Klotz U, Duka T, Dorow R, Doenicke A (1985) Flunitrazepam and lormetazepam do not affect the pharmacokinetics of the benzodiazepine antagonist Ro 15–1788. Br J Clin Pharmacol 19:95–98

    Google Scholar 

  • Kopin I (1981) Catecholamines, adrenal hormones, and stress. In: Krieger H (ed) Neuroendocrinology. Sinauer Associates, Sunderland, pp 159–166

    Google Scholar 

  • Krohne HW (1974) Untersuchungen mit einer deutschen Form der Repression-Sensitization-Skala. Z Klin Psychol Psychother 3:238–260

    Google Scholar 

  • Levi L (1961) A new stress tolerance test with simultaneous study of physiological and psychological variables. Acta Endocrinol (Kbh) 37:38–44

    Google Scholar 

  • Levi L (1972) Stress and distress in response to psychosocial stimuli. Acta Med Scand 528 suppl:151–156

    Google Scholar 

  • Lukas SE, Griffiths RR (1984) Precipitated diazepam withdrawal in baboons: Effects of dose and duration of diazepam exposure. Eur J Pharmacol 100:163–171

    Google Scholar 

  • Major LF, Hawley RJ, Linnoila M (1984) The role of the central noradrenergic nervous system in the mediation of the ethanol intoxication and ethanol withdrawal syndrome. Psychopharmacol Bull 20:487

    Google Scholar 

  • Michalova C, Hrubes V, Benes V (1966) The influence of chlordiazepoxide on biochemical reactions to experimental stress in rats. Activ Nerv Sup (Praha) 8:458–459

    Google Scholar 

  • Pellow S, File SE (1984) Multiple sites of action for anxiogenic drugs: Behavioural, electrophysiological and biochemical correlations. Psychopharmacology 83:304–315

    Google Scholar 

  • Petursson H, Lader MH (1981) Withdrawal from long-term benzodiazepine treatment. Br Med J 283:643–645

    Google Scholar 

  • Picotti GB, Corli O, Galva MD, Bondiolotti GP, Carruba MO (1982) Effects of oral chlordemethyldiazepam on plasma adrenaline and noradrenaline and cardiovascular reactivity in preoperative patients. Eur J Clin Pharmacol 23:383–388

    Google Scholar 

  • Schöpf J (1983) Withdrawal phenomena after long-term administration of benzodiazepines. A review of recent investigations. Pharmacopsychiatr 16:1–8

    Google Scholar 

  • Schöpf J, Laurian S, Le PK and Gaillard JM (1984) Intrinsic activity of the benzodiazepine antagonist Ro 15–1788 in man: An electrophysiological investigation. Pharmacopsychiatr 17:79–83

    Google Scholar 

  • Smith DE (1979) Importance of grandual dosage reduction following low dose benzodiazepine therapy. Newslett Calif Soc Treat Alcohol Drug Depend 6:1–3

    Google Scholar 

  • Taylor KM, Laverty R (1969) The effect of chloridiazepoxide, diazepam and nitrazepam on catecholamine metabolism in regions of the rat brain. Eur J Pharmacol 8:296–301

    Google Scholar 

  • Timm U, Zell M (1983) Determination of the benzodiazepine antagonist Ro 15–1788 in plasma by high-performance liquid chromatography with UV detection. Arzneim Forsch (Drug Res) 33:358–362

    Google Scholar 

  • Vogel WH, Miller J, DeTurck H and Routzahn B (1984) Effects of psychoactive drugs on plasma catecholamines during stress in rats. Neuropsychopharmacology 23:1105–1108

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Duka, T., Ackenheil, M., Noderer, J. et al. Changes in noradrenaline plasma levels and behavioural responses induced by benzodiazepine agonists with the benzodiazepine antagonist Ro 15-1788. Psychopharmacology 90, 351–357 (1986). https://doi.org/10.1007/BF00179190

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00179190

Key words

Navigation