Abstract
The effects of lormetazepam (0.03 mg/kg IV) a benzodiazepine (BZ) derivative in combination with ZK 93 426 (0.04 mg/kg IV) a β-carboline, benzodiazepine receptor antagonist were evaluated in humans. Independently, the effects of ZK 93 426 on its own were investigated. A psychometric test battery to evaluate sedation (visual analog scales (VAS), anxiolysis (state-trait-anxiety inventory scale (STAIG X1) and cognitive functions [logical reasoning test (LR), letter detection test (LD)] was applied before and several hours after initiation of treatment. Multiple sleep latency test (MSLT), which measures day time sleepiness, was also applied. Vigilosomnograms analysed from standard EEG recordings were evaluated shortly before and for 1 h after treatment. Treatment started with an intravenous injection of either lormetazepam (LMZ) or placebo (PLA), which was followed 30 min later by administration of either ZK 93 426 or placebo; thus four treatment groups were created (PLA + PLA, LMZ + PLA, LMZ + ZK 93 426 and PLA + ZK 93 426). ZK 93 426 antagonized the sedative and hypnotic effect of LMZ as estimated by MSLT and vigilosomnograms, respectively. Impairment of cognitive functions (LR and LD) induced by LMZ was also antagonized by ZK 93 426. ZK 93 426 had no effect on the changes in the time estimation seen in the LMZ group. Furthermore, ZK 93 426 on its own increased vigilance (alertness) as measured by the vigilosomnogram. A competitive antagonism at the benzodiazepine binding site between ZK 93 426 and LMZ is suggested by their combination effects; the intrinsic activity of ZK 93 426 seems to be due to its weak partial inverse agonist component.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baddeley AD (1968) A 3 min reasoning test based on grammatical transformation. Psychon Sci 10:341–342
Brosan L, Broadbent D, Nutt D, Broadbent M (1986) Performance effects of diazepam during and after prolonged administration. Psychol Med 16:510–522
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
Dorow R, Berenberg D, Duka T, Sauerbrey N (1987) Amnesic effects of lormetazepam and their reversal by the benzodiazepine antagonist Ro 15–1788. Psychopharmacology 93:507–514
Duka T, Höllt V, Herz A (1979) In vivo receptor occupation by benzodiazepines and correlation with the pharmacological effect. Brain Res 179:147–156
Duka T, Ackenheil M, Noderer J, Doenicke A, Dorow R (1986) Changes in noradrenaline plasma levels and behavioural responses induced by benzodiazepine agonists with the benzodiazepine antagonist Ro 15–1788. Psychopharmacology 90:351–357
Duka T, Stephens DN, Krause W, Dorow R (1987) Human studies on the benzodiazepine receptor antagonist β-carboline ZK 93 426: Preliminary observations on psychotropic activity. Psychopharmacology 93:421–427
Elsass P, Mellerup ET, Rafaelsen OJ, Theilgaard A (1979) Lithium effects on time estimation and mood on manic-melancholic patients. A study of diurnal variations. Acta Psychiatr Scand 60:263–271
File SE, Pellow S, Jensen LH (1986) Actions of the β-carboline ZK 93 426 in animal test of anxiety and the holeboard: interactions with Ro 15–1788. J Neural Transm 65:103–114
Ghoneim MM, Mewaldt SP, Hinrichs JV (1984) Dose-response analysis of the behavioral effects of diazepam: II. Psychomotor performance, cognition and mood. Psychopharmacology 82:296–300
Höller L, Riemer H (1986) Comparison of visual analysis and automatic sleep stage scoring (Oxford Medilog 9000 System). Eur Neurol [Suppl] 2:36–45
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
Jensen LH, Petersen EN, Braestrup C, Honoré T, Kehr W, Stephens DN, Schneider H, Seidelmann D, Schmiechen R (1984) Evaluation of the β-carboline ZK 93 426 as a benzodiazepine receptor antagonist. Psychopharmacology 83:249–256
Lister RG (1985) The amnesic action of benzodiazepines in man. Neurosci Biobehav Rev 9:87–93
Mohler H, Okada T (1977) Benzodiazepine receptors: demonstration in the CNS. Science 198:849–851
Pellow S, File SE (1986) Intrinsic actions of the benzodiazepine receptor antagonist Ro 15–1788. Psychopharmacology 88:1–11
Richardson G, Carskadon MA, Flagg W, van den Hoed J, Dement WC, Mitler MM (1978) Excessive daytime sleepiness in man, multiple sleep latency measurement in narcoleptic and control subjects. Electroencephalogr Clin Neurophysiol 45:621–627
Schöpf J, Laurian S, Le PK, Gaillard JM (1984) Intrinsic activity of the benzodiazepine antagonist Ro 15–1788 in man: an electrophysiological investigation. Pharmacopsychiatry 17:79–83
Spielberger CD, Gorsuch RL, Lushene RE (1966) Manual for the State Trait Anxiety Inventory. Consulting Psychologist Press, Palo Alto, California
Squires RF, Braestrup C (1977) Benzodiazepine receptors in rat brain. Nature 266:732–734
Stephan K, Dorow R (1986) The influence of the new antidepressant rolipram on alertness, performance and mood in healthy volunteers varied with time of day and diurnal type of subject. In: Labrecque G (ed) Biological rhythms and medications. Annual review of chronopharmacology, vol 3. Pergamon Press, Oxford New York, pp 437–440
Stephens DN, Shearman GT, Kehr W (1984) Discriminative stimulus properties of β-carbolines characterized as agonists and inverse agonists at central benzodiazepine receptors. Psychopharmacology 83:233–239
Stephens DN, Kehr W, Duka T (1986) Anxiolytic and anxiogenic β-carbolines: tools for the study of anxiety mechanisms. In: Biggio G, Costa E (eds) Gabaergic transmission and anxiety. Raven Press, New York
Ziegler G, Ludwig L, Fritz G (1986) Effects of the specific benzodiazepine antagonist Ro 15–1788 on sleep. Pharmacopsychiatry 19:200–201
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Duka, T., Goerke, D., Dorow, R. et al. Human studies on the benzodiazepine receptor antagonist β-carboline ZK 93 426: antagonism of lormetazepam's psychotropic effects. Psychopharmacology 95, 463–471 (1988). https://doi.org/10.1007/BF00172956
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00172956