Abstract
The effects of flumazenil, a benzodiazepine receptor antagonist, on triazolam- and zolpidem-induced memory impairment were investigated. Sixty subjects received oral triazolam 0.5 mg, zolpidem 20.0 mg, or placebo at 10 a.m. (n=20 per drug). Ninety minutes later, half of the subjects (n=10) in each oral drug group were administered flumazenil 1.0 mg, while the remaining half received placebo (normal saline), through indwelling venous catheters. Learning/memory tests (including Simulated Escape, Restricted Reminding, Paired-Associates, and Repeated Acquisition) were administered at that time, and at 1.5-h intervals over the next 6 h. Triazolam/placebo and zolpidem/placebo drug combinations impaired memory on all tests (allPs<0.05). However, the triazolam/flumazenil and zolpidem/flumazenil groups showed no evidence of impairment during any test session. These results demonstrate that flumazenil 1.0 mg rapidly and lastingly reverses memory impairment caused by agonists of the benzodiazepine receptor. Furthermore, nonsignificant trends suggested that performance of the placebo/flumazenil group was consistently better than that of the placebo/placebo group, denoting a possible role of endogenous benzodiazepine agonists in natural sleep/wake processes.
Similar content being viewed by others
References
Balkin TJ, O'Donnell VM, Kamimori GH, Redmond DP, Belenky G (1989) Sleep inertia following triazolam-induced recovery sleep. Hum Psychopharmacol 4:291–296
Balkin TJ, O'Donnell VM, Wesensten N, McCann U, Belenky G (1992) Comparison of the daytime sleep and performance effects of zolpidem versus triazolam. Psychopharmacology 107:83–88
Berlin I, Warot D, Hergueta T, Molinier P, Bagot C, Puech AJ (1993) Comparison of the effects of zolpidem and triazolam on memory functions, psychomotor performances, and postural sway in healthy subjects. J Clin Psychopharmacol 13:100–106
Bonetti EP, Pieri L, Cumin R, Schaffner R, Pieri M, Gamzu ER, Muller RKM, Haefely W (1982) Benzodiazepine antagonist Ro 15-1788: neurological and behavioral effects. Psychopharmacology 78:8–18
Brogden RN, Goa KL (1991) Flumazenil. A reappraisal of its pharmacological properties and therapeutic efficacy as a benzodiazepine antagonist. Drugs 42:1061–1089
Burkhart KK, Kulig KW (1990) The diagnostic utility of flumazenil (a benzodiazepine antagonist) in coma of unknown etiology. Ann Emerg Med 19:319–321
Buschke H, Fuld PA (1974) Evaluating storage, retention, and retrieval in disordered memory and learning. Neurology 24:1019–1025
Curran HV, Birch B (1991) Differentiating the sedative, psychomotor and amnestic effects of benzodiazepines: a study with midazolam and the benzodiazepine antagonist, flumazenil. Psychopharmacology 103:519–523
Darragh A, Lambe R, Kenny M, Brick I (1983) Tolerance of healthy volunteers to intravenous administration of the benzodiazepine antagonist Ro 15-1788. Eur J Clin Pharmacol 24:569–570
Dixon WJ (1985) BMDP statistical software manual. University of California Press, Berkeley, Los Angeles, London.
Dorow R, Berenberg D, Duka T, Sauerbrey N (1987) Amnestic effects of lormetazepam and their reversal by the benzodiazepine antagonist Ro 15-1788. Psychopharmacology 93:507–514
Dunton AW, Schwam E, Pitman V, McGrath J, Hendler J, Siegel J (1988) Flumazenil: U.S. clinical pharmacology studies. Eur J Anaesthesiol S2:81–95
Farb DH, Borden LA, Chan CY, Czajkowski CM, Gibbs TT, Schiller GD (1984) Modulation of neuronal function through benzodiazepine receptors: biochemical and electrophysiological studies of neurons in primary monolayer cell culture. Ann NY Acad Sci 435:1–31
File SE, Baldwin HA (1987) Flumazenil: a possible treatment for benzodiazepine withdrawal anxiety. Lancet 2:106–107
File SE, Pellow S (1986) Intrinsic actions of the benzodiazepine receptor antagonist Ro 15-1788. Psychopharmacology 88:1–11
Friedman H, Greenblatt DJ, Burstein ES, Harmatz JS, Shader RI (1986) Population study of triazolam pharmacokinetics. Br J Clin Pharmacol 22:639–642
Gallager DW, Heninger K, Heninger G (1986) Periodic benzodiazepine antagonist administration prevents benzodiazepine withdrawal symptoms in primates. Eur J Pharmacol 132:31–38
Gentil V, Gorenstein C, Camargo CHP, Singer JM (1989) Effects of flunitrazepam on memory and their reversal by two antagonists. J Clin Psychopharmacol 9:191–197
Ghoneim MM (1992) The reversal of benzodiazepine-induced amnesia by flumazenil: a review. Curr Ther Res 52:757–767
Grimm G, Katzenschlager R, Holzner F, Ferenci P, Schneeweiss B, Laggner A, Lenz K, Druml W, Madl C (1988) Effect of flumazenil in hepatic encephalopathy. Eur J Anaesthesiol S2:147–149
Kelly C, Egner J, Rubin J (1988) Successful treatment of triazolam overdose with Ro 15-1788. S Afr Med J 73:442
Kirk RE (1982) Experimental design: procedures for the behavioral sciences, 2nd edn. Brooks/Cole, Belmont, Calif.
Klotz U, Ziegler G, Reimann IW (1984) Pharmacokinetics of the selective benzodiazepine antagonist Ro 15-1788 in man. Eur J Clin Pharmacol 27:115–117
Langer SZ, Arbilla S, Scatton B, Niddam R, Dubois A (1988) Receptors involved in the mechanism of action of zolpidem. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders: a novel experimental and therapeutic approach (L.E.R.S. Monograph Series Volume 6). Raven Press, New York, pp 55–70
Lauven PM, Schwilden H, Stoeckel H, Greenblatt, DJ (1985) The effects of a benzodiazepine antagonist Ro 15-1788 in the presence of stable concentrations of midazolam. Anesthesiology 63:61–64
Lheureux P, Debailleul G, De Witte O, Askenasi R (1990) Zolpidem intoxication mimicking narcotic overdose: response to flumazenil. Hum Exp Toxicol 9:105–107
McKay AC, McKinney MS, Clarke RSJ (1990) Effect of flumazenil on midazolam-induced amnesia. Br J Anaesth 65:190–196
Meier R, Gyr K (1988) Treatment of hepatic encephalopathy (HE) with the benzodiazepine antagonist flumazenil: a pilot study. Eur J Anaesthesiol S2:139–146
O'Boyle C, Lambe R, Darragh A, Taffe W, Brick I, Kenny M (1983) Ro 15-1788 antagonizes the effects of diazepam in man without affecting its bioavailability. Br J Anaesth 55:349–355
O'Donnell VM (1981) Neurochemical correlates of memory function in Korsakoff's syndrome and Alzheimer's disease. PhD thesis, Department of Psychology, University of Houston, Houston, Texas
O'Donnell VM, Balkin TJ, Andrade JR, Simon LM, Kamimori GH, Redmond DP, Belenky G (1988) Effects of triazolam on performance and sleep in a model of transient insomnia. Hum Perform 1:146–160
Patat A, Naef MM, Van Gessel E, Forster A, Dubruc C, Rosenzweig P (1994) Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic. Clin Pharmacol Ther 6:430–436
Penetar D, Belenky G, Garigan JJ, Redmond DP (1989) Triazolam impairs learning and fails to improve sleep in a long-range aerial deployment. Aviat Space Env Med 60:594–598
Physician's Desk Reference (1994) PDR(R) Library on CD-ROM(TM). Medical Economics Company, Montvale, N.J.
Polc P, Laurent JP, Scherschlicht R, Haefeley W (1981) Electrophysiological studies on the specific benzodiazepine antagonist Ro 15-1788. Arch Pharmacol 316:317–325
Preston GC, Ward CE, Broks P, Traub M, Stahl SM (1989) Effects of lorazepam on memory, attention and sedation in man: antagonism by Ro 15-1788. Psychopharmacology 97:222–227
Roehrs T, Merlotti L, Zorick F, Roth T (1994) Sedative, memory, and performance effects of hypnotics. Psychopharmacology 116:130–134
Roncari G, Ziegler WH, Guentert TW (1986) Pharmacokinetics of the new benzodiazepine antagonist Ro 15-1788 in man following intravenous and oral administration. Br J Clin Pharmacol 22:421–428
Rothstein JD, Guidotti A, Tinuper P, Cortelli P, Avoni P, Plazzi G, Lugaresi E, Schoch P, Montagna P (1992) Endogenous benzodiazepine receptor ligands in idiopathic recurring stupor. Lancet 340:1002–1004
Sharief MK, Sander JWAS, Shorvon SD (1993) The effect of oral flumazenil on interictal epileptic activity: results of a double-blind, placebo-controlled study. Epilepsy Res 15:53–60
Short TG, Galletly DC (1989) Residual psychomotor effects following reversal of midazolam sedation with flumazenil. Anaesth Intensive Care 17:290–297
Siegart W, Schuster A (1984) Affinity of various ligands for benzodiazepine receptors in rat cerebellum and hippocampus. Biochem Pharmacol 33:4033–4038
Thenot JP, Hermann P, Durand A, Burke JT, Allen J, Garrigou D, Vajta S, Albin H, Thebault JJ, Olive G, Warrington SJ (1988) Pharmacokinetics and metabolism of zolpidem in various animal species and in humans. In: Sauvanet JP, Langer SZ, Morselli PL (eds) Imidazopyridines in sleep disorders: A novel experimental and therapeutic approach (L.E.R.S. Monograph Series Volume 6). Raven Press, New York, pp 139–153
Thorne DR, Genser SG, Sing HC, Hegge FW (1985) The Walter Reed performance assessment battery. Neurobehav Toxicol Teratol 7:415–418
Unseld E, Fischer C, Rothemund E, Klotz U (1990) Occurrence of “natural” diazepam in human brain. Biochem Pharmacol 39:210–212
Young WS, Niehoff D, Kuhar MJ, Beer B, Lippa AS (1981) Multiple benzodiazepine receptor localization by light microscopic radiohistochemistry. J Pharmacol Exp Ther 216:425–430
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Wesensten, N.J., Balkin, T.J., Davis, H.Q. et al. Reversal of triazolam- and zolpidem-induced memory impairment by flumazenil. Psychopharmacology 121, 242–249 (1995). https://doi.org/10.1007/BF02245635
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02245635