Abstract
The physiological function of benzodiazepine (BDZ) receptors includes regulation of sleep and neuroendocrine activity. Most of the pharmacological effects of BDZ are blocked by flumazenil. However, recent neurological and behavioral studies suggest that flumazenil has its own central intrinsic activity. This issue was addressed in a study of the sleep EEG and the nocturnal secretion of growth hormone and cortisol in ten normal male controls, who were given flumazenil either alone or in combination with the BDZ agonist midazolam, placebo and midazolam alone. Flumazenil prompted an increase in sleep onset latency, a decrease in slow wave sleep and an increase in wakefulness. Plasma cortisol concentrations after flumazenil administration were lower than after midazolam. Both flumazenil and midazolam decreased nocturnal growth hormone secretion. After simultaneous application of both BDZ receptor ligands the growth hormone blunting was amplified. Our study demonstrates that at the level of the sleep EEG and neuroendocrine activity flumazenil is capable of exerting both agonistic and inverse agonistic or antagonistic effects.
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References
Borbély AA, Mattmann P, Loepfe M, Strauch I, Lehmann D (1985) Effect of benzodiazepine hypnotics on all-night sleep EEG spectra. Hum Neurobiol 4:189–194
Christensen P, Lolk A, Gram LF, Kragh-Sorensen P (1992) Benzodiazepine-induced sedation and cortisol suppression. Psychopharmacology 106:511–516
Copinschi G, Van Onderbergen A, L'Hermite-Balériaux M, Szyper M, Caufriez A, Bosson D, L'Hermite M, Robyn C, Turek FW, Van Cauter E (1990) Effects of the short-acting benzodiazepine triazolam, taken at bedtime, on circadian and sleep-related hormonal profiles in normal men. Sleep 13:232–244
Darragh A, Tormey WP, Dolphin C (1979) The effects of diazepam on sleep, and on the nocturnal release of growth hormone, prolactin, ACTH and cortisol. Br J Clin Pharmacol 8:90–92
Darragh A, Lambe R, O'Boyle C, Kenny M, Brick I (1983) Absence of central effects in man of the benzodiazepine antagonist Ro 15–1788. Psychopharmacology 80:192–195
Gaillard JM, Blois R (1989) Differential effects of flunitrazepam on human sleep in combination with flumazenil. Sleep 12:120–132
Guldner J, Steiger A, Rothe B, Holsboer F (1991) Influence of the partial benzodiazepine agonist bretazenil on sleep EEG and nocturnal secretion of cortisol and growth hormone. Sleep Res 20A: 137
Haefely WE (1989) Pharmacology of the benzodiazepine receptor. Eur Arch Psychiatr Neurol Sci 238:294–301
Holsboer F, Von Bardeleben U, Steiger A (1988) Effects of intravenous corticotropin-releasing hormone upon sleep related growth hormone surge and sleep EEG in man. Neuroendocrinology 48:32–38
Kales A, Soldatos CR, Bixler EO, Kales JD, Vela Bueno A (1988) Diazepam effects on sleep and withdrawal phenomena. J Clin Psychopharmacol 8:340–345
Klotz U, Ziegler G, Ludwig L, Reimann I (1985) Pharmacodynamic interaction between midazolam and a specific benzodiazepine antagonist in man. J Clin Pharmacol 27:400–406
Krieger J, Mangen P, Kurtz D (1983) Effects of midazolam on sleep in normal subjects. Arzneimittelforschung 33:1000–1002
Owens MJ, Bisette G, Nemeroff CB (1989) Acute effects of alprazolam and adinazolam on the concentrations of CRF in the rat brain. Synapse 4:196–202
Pohorecky L, Cotler S, Carbone JJ, Roberts P (1988) Factors modifying the effect of diazepam on plasma corticosterone levels in rats. Life Sci 43:2159–2167
Polc P (1988) Electrophysiology of benzodiazepine receptor ligands: multiple mechanism and sites of action. Prog Neurobiol 31:350–423
Rechtschaffen A, Kales A (eds) (1968) A manual of standardized terminology techniques and scoring system for sleep stages of human subjects. US Department of Health, Education and Welfare, Neurological Information Network, Bethesda, MD
Sassin JF, Parker DC, Mace JW, Gotlin RW, Johnson LC, Rossman LG (1969) Human growth hormone release: relation to slowwave sleep and sleep-waking cycles. Science 165:513–515
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
Steiger A, Herth T, Holsboer F (1987) Sleep-electroencephalography and the secretion of cortisol and growth hormone in normal controls. Acta Endocrinol Copenh 116:36–42
Weitzman ED (1976) Circadian rhythms and episodic hormone secretion in man. Annu Rev Med 27:225–243
Weitzman ED, Pollak CP (1982) Effects of flurazepam on sleep and growth hormone release during sleep in healthy subjects. Sleep 5:343–349
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Steiger, A., Guldner, J., Lauer, C.J. et al. Flumazenil exerts intrinsic activity on sleep EEG and nocturnal hormone secretion in normal controls. Psychopharmacology 113, 334–338 (1994). https://doi.org/10.1007/BF02245206
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DOI: https://doi.org/10.1007/BF02245206