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Cerebral-activating (EEG) properties of two inverse agonists and of an antagonist at the benzodiazepine receptor in the rat

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Summary

In order to assess the effects of inverse benzodiazepine agonists and antagonists on brain function, computerized EEG (CEEG) analysis was performed in rats following the i. p. administration of SR 95195 (7-phenyl-3-methyl-1,2,4 triazolo-[4,3-b]pyridazine) and CGS 8216 (2-phenylpyrazolo-[4,3c]-quinoline-3-[5H]-one) two benzodiazepine receptor inverse agonists (BRIAGs) and of flumazepil (Ro 15-1788), a benzodiazepine receptor antagonist (BRANT). The EEG effects of SR 95195 (3, 10, 30 and 60 mg/kg), CGS 8216 (10 and 30 mg/kg) and flumazepil (3, 10, 30 and 60 mg/kg) were compared to those of the psychostimulant drugs DL-amphetamine (0.1, 0.3 and 1 mg/kg), and caffeine (10 and 30 mg/kg) and those of aniracetam (100 and 300 mg/kg), a nootropic pyrrolidone derivative. The CEEG profiles of SR 95195, CGS 8216 and flumazepil were mainly characterized by a power increase in the 20–32 Hz frequency range and by a power reduction in the 8–16 Hz range. These effects were quite similar to those of the psychostimulants DL-amphetamine and caffeine as well as to those of the nootropic aniracetam. Other psychotropic drugs with CNS-depressant properties, namely diazepam (10 mg/kg p. o.), pentobarbital (30 mg/kg p. o.), chlorpromazine (10 mg/kg i.p.) and imipramine (10 mg/kg i.p.) induced quite different EEG power modifications. These results show that BRIAGs and BRANTs possess a marked intrinsic activity at the central level and suggest that this activity is CNS-activating in nature.

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References

  • Bente D, Glatthaar G, Ulrich G, Lewinsky M (1978) Piracetam and vigilance: electroencephalographic and clinical results of longterm therapy in gerontopsychiatric patients. Arzneim Forsch 28:1529–1531

    Google Scholar 

  • Bieck PR, Antonin KH, Britzelmeier C, Cremer C, Gleiter C, Nilsson E, Schoenleber W (1984) Human pharmacology of CGS 8216, a benzodiazepine antagonist. Clin Neuropharmacol 7 (Suppl 1):674–675

    Google Scholar 

  • Bizière K, Bourguignon JJ, Chambon JP, Heaulme M, Perio A, Tebib S, Wermuth CG (1987) A 7-phenyl substitute triazolopyridazine has inverse agonist activity at the benzodiazepine receptor site. Brit J Pharmacol 90:183–190

    Google Scholar 

  • Boakes RJ, Bradley PB, Candy JM (1979) Interactions of (+)-amphetamine and chlorpromazine on neurones in the lower brain stem of the rat. Brit J Pharmacol 67:165–171

    Google Scholar 

  • Boast CA, Bernard PS, Barbaz BS, Bergen KM (1983) The neuropharmacology of various diazepam antagonists. Neuropharmacology 22:1511–1521

    Google Scholar 

  • Bonetii EP, Pieri L, Cumin R, Schaffner R, Pieri M, Gamzu ER, Müller RKM, Haefely W (1982) Benzodiazepine antagonist Ro 15–1788: neurological and behavioral effects. Psychopharmacology 78:8–18

    Google Scholar 

  • Corda MG, Giorgi O, Gatta F, Biggio G (1985) Long-lasting proconflict effect induced by chronic administration of the beta-carboline derivative FG 7142. Neurosci Lett 62:237–240

    Google Scholar 

  • Cumin R, Bandle EF, Gamzu E, Haefely WE (1982) Effects of the novel compound aniracetam (Ro 13–5057) upon impaired learning and memory in rodents. Psychopharmacology 78:104–111

    Google Scholar 

  • Dantzer R (1977) Behavioral effects of benzodiazepines: a review. Biobehav Rev 1:71–86

    Google Scholar 

  • 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

    Google Scholar 

  • Depoortere H, Decobert M, Honore L (1983) Drug effects on the EEG of various species of laboratory animals. Neuropsychobiology 9:244–249

    Google Scholar 

  • Depoortere H, Zivkovic B, Lloyd KG, Sanger DJ, Perrault G, Langer SZ, Bartholini G (1986) Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. J Pharmacol Exp Ther 237:649–658

    CAS  PubMed  Google Scholar 

  • Fairchild MD, Jenden DJ, Mickey MR, Yale C (1980) The quantitative measurements of changes in EEG frequency spectra produced in the cat by sedative-hypnotics and neuroleptics. Electroencephalogr Clin Neurophysiol 49:382–390

    Google Scholar 

  • Fibiger HC (1982) The organization and some projections of cholinergic neurons of the mammalian forebrain. Brain Res Rev 4:327–388

    Google Scholar 

  • File SE (1983) Proconvulsant action of CGS 8216. Neurosci Lett 35:317–320

    Google Scholar 

  • File SE, Lister RG (1983) Interactions of ethyl-\-carboline-3–3-carboxylate and Ro 15–1788 with CGS 8216 in an animal model of anxiety. Neurosci Lett 39:91–94

    Google Scholar 

  • File SE, Pellow S (1984) The anxiogenic action of FG 7142 in the social interaction test is reversed by chlordiazepoxide and Ro 15–1788 but not by CGS 8216. Arch Int Pharmacodyn Ther 271:198–205

    Google Scholar 

  • File SE, Pellow S (1986) Intrinsic actions of the benzodiazepine receptor antagonist Ro 15–1788. Psychopharmacology 88:1–11

    Google Scholar 

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

    Google Scholar 

  • File SE, Dingemanse J, Friedman HL, Greenblatt DJ (1986) Chronic treatment with Ro 15–1788 distinguishes between its benzodiazepine antagonist, agonist and inverse agonist properties. Psychopharmacology 89:113–117

    Google Scholar 

  • Gaillard JM, Blois R (1983) Effects of the benzodiazepine antagonist Ro 15–1788 on flunitrazepam-induced sleep changes. Brit J Clin Pharmacol 15:529–536

    Google Scholar 

  • Gainotti G, Benedetti N, Caltagirone C, Nocentini U (1986) Cognitive improvement in clinical trials with nootropic drugs: when can it be expected and how to clarify its meaning. Clin Neuropharmacol 9 (suppl 3):65–69

    Google Scholar 

  • Gerbrandt LK, Lawrence JC, Eckardt MJ, Lloyd RL (1978) Origin of the neocortically monitored theta rhythm in the curarized rat. Electroencephalogr Clin Neurophysiol 45:454–467

    Google Scholar 

  • Groves PM, Tepper JM (1983) Neuronal mechanisms of action of amphetamine. In: Creese I (ed) Stimulants: neurochemical, behavioral and clinical perspectives. Raven Press, New York, pp 81–129

    Google Scholar 

  • Higgit A, Lader M, Fonagy P (1986) The effects of the benzodiazepine antagonist Ro 15–1788 on psychophysiological performance and subjective measures in normal subjects. Psychopharmacology 89:395–403

    Google Scholar 

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

    Google Scholar 

  • Itil TM, Hugue M (1979) Computer EEG profiles of anxiolytics (quantitative pharmaco-EEG in the development of new anxiolytics). In: Fielding S, Lal H (eds) Industrial pharmacology. Futura Publishing Co, New York, pp 281–316

    Google Scholar 

  • Itil TM, Soldatos C, Bozak M, Ramadanoglu E, Dayican G, Morgan V, Menon GN (1979) CNS effects of ISF-2522, a new nootropic (a phase I safety and CNS efficacy study with quantitative pharmaco-EEG and pharmacopsychology). Curr Ther Res 26:525–538

    Google Scholar 

  • Itil TM, Menon GN, Bozak M, Songar A (1982) The effects of oxiracetam (ISF 2522) in patients with organic brain syndrome (a double blind controlled study with piracetam). Drug Devel Res 2:447–462

    Google Scholar 

  • Jensen LH, Petersen EN, Braestrup C (1983) Audiogenic seizures in DBA/2 mice discriminate sensitively between low efficacy benzodiazepine receptor agonists and inverse agonists. Life Sci 33:393–399

    Google Scholar 

  • Jensen LH, Petersen EN, Braestrup C, Honoré T, Kehr W, Stephens DN, Schneider H, Seidelmann D, Schmiechen R (1984) Evaluation of the \-carboline ZK 93426 as a benzodiazepine receptor antagonist. Psychopharmacology 83:249–256

    Google Scholar 

  • Johnston MV, McKinney M, Coyle JT (1979) Evidence for a cholinergic projection to neocortex from neurons in the basal forebrain. Proc Nat Acad Sci [USA] 76:5392–5396

    Google Scholar 

  • Komiskey HL, Cook TM, Lin C-F, Hayton WL (1981) Impairment of learning or memory in the mature and old rat by diazepam. Psychopharmacology 73:304–305

    Google Scholar 

  • Koob GF, Braestrup C, Thatcher Britton K (1986) The effects of FG 7142 and Ro 15–1788 on the release of punished responding produced by chlordiazepoxide and ethanol in the rat. Psychopharmacology 90:173–178

    Google Scholar 

  • Kuczenski R (1983) Biochemical actions of amphetamine and other stimulants. In: Creese I (ed) Stimulants: neurochemical, behavioral and clinical perspectives. Raven Press, New York, pp 31–61

    Google Scholar 

  • Kuhn FJ, Schingnitz G, Lehr E, Montagna E, Hinzen HD, Giachetti A (1988) Pharmacology of WEB 1881-FU, a central cholinergic agent, which enhances cognition and cerebral metabolism. Arch Int Pharmacodyn 292:13–34

    Google Scholar 

  • Liljequist R, Linnoila M, Mattila MJ (1978) Effects of diazepam and chlorpromazine on memory and learning in man. Eur J Clin Pharmacol 13:339–344

    Google Scholar 

  • Little HJ, Nutt PJ, Taylor SC (1984) Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling. Br J Pharmacol 83:951–958

    Google Scholar 

  • Marks GA, Farber J, Roffwarg HP (1980) Metencephalic localization of pento-geniculo-occipital waves in the albino rat. Exp Neurol 69:667–677

    Google Scholar 

  • Massotti M, Lucantoni D, Caporali HG, Mele L, Gatta F (1985) Supraspinal convulsions induced by inverse benzodiazepine agonists in rabbits. J Pharmacol Exp Ther 234:274–279

    Google Scholar 

  • Möhler H, Okada T (1977) Benzodiazepine receptor in the central nervous system. Science 198:849–851

    Google Scholar 

  • Neal H, Bond A (1985) Quantitative electrocortical changes in the rat induced by phencyclidine and other stimulants. Neuropharmacology 24:317–323

    Google Scholar 

  • Nikolova M (1981) Experimental electroencephalographic study of piracetam in cats. Meth Find Exptl Clin Pharmacol 3:367–375

    Google Scholar 

  • Nutt DJ, Cowen PJ, Little HJ (1982) Unusual interactions of benzodiazepine antagonists. Nature 295:436–438

    Google Scholar 

  • Ongini E, Barzhagi C, Marzanatti M (1983) Intrinsic and antagonistic effects of \-carboline FG 7142 on behavioral and EEG actions of benzodiazepines and pentobarbital in cats. Eur J Pharmacol 95:125–129

    Google Scholar 

  • Pepeu G (1973) The release of acetycholine from the brain: an approach to the study of the central cholinergic mechanisms. Prog Neurobiol 2:257–288

    Google Scholar 

  • Petersen EN, Jensen LH, Honoré T, Braestrup C (1983) Differential pharmacological effects of benzodiazepine receptor inverse agonists. In: Biggio G, Costa E (eds) Benzodiazepine recognition site ligands: biochemistry and pharmacology. Raven, New York, pp 57–64

    Google Scholar 

  • Phillis JW (1968) Acetylcholine release from the cerebral cortex: its role in cortical arousal. Brain Res 7:378–389

    Google Scholar 

  • Phillis JW, Edstrom JP, Kostopoulos GK, Kirkpatrick JR (1979) Effects of adenosine and adenine nucleotides on synaptic transmission in the cerebral cortex. Can J Physiol Pharmacol 57:1289–1312

    Google Scholar 

  • Pilch H, Müller WE (1988) Piracetam elevates muscarinic cholinergic receptor density in the frontal cortex of aged but not of young mice. Psychopharmacology 94:74–78

    Google Scholar 

  • Pole P, Laurent J-P, Scherschlicht R, Haefely W (1981) Electrophysiological studies on the specific benzodiazepine antagonist Ro 15–1788. Naunyn-Schmiedeberg's Arch Pharmacol 316:317–325

    Google Scholar 

  • Pole P, Bonetti EP, Schaffner R, Haefely W (1982) A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro 15–1788, benzodiazepine tranquilizers, \-carbolines, and phenobarbitone. Naunyn-Schmiedeberg's Arch Pharmacol 321:260–264

    Google Scholar 

  • Pontecorvo MJ, Evans HL (1985) Effects of aniracetam upon the delayed matching-to-sample performance of monkeys and pigeons. In: Olton DS, Gamzu E, Corkin S (eds) Memory dysfunctions: an integration of animal and human research from preclinical and clinical perspectives. Ann NY Acad Sci 444:406–427

  • Saano V, Airaksinen MM (1982) Binding of \-carbolines and caffeine on benzodiazepine receptors: correlations to convulsions and tremor. Acta Pharmacol Toxicol 51:300–308

    Google Scholar 

  • Saletu B, Grünberger J (1980) Antihypoxydotic and nootropic drugs: proof of their encephalotropic and pharmacodynamic properties by quantitative EEG investigations. Prog Neuropsychopharmacol 4:469–489

    Google Scholar 

  • Saletu B, Grünberger J (1985) Memory dysfunctions and vigilance: neurophysiological and psychopharmacological aspects. In: Olton DS, Gamzu E, Corkin S (eds) Memory dysfunctions: an integration of animal and human research from preclinical and clinical perspectives. Ann NY Acad Sci 444:406–427

  • Sand M, Pinelli G, Ricci P, Penne A, Zeneroli ML, Baraldi M (1985) Evidence that 2-phenylpyrazolo[4,3-c]quinolin-3(5h)-one antagonises pharmacological, electrophysiological and biochemical effects of diazepam in rats. Neuropharmacology 24:99–105

    Google Scholar 

  • Santucci V, Rocher D, Veyrun J, Bizière K (1986) Quantitative electroencephalographic profile of 3-(4-hydroxy-1-piperidinyl)-6-(2,4-dichlorophenyl)-pyridazine (SR 41378), in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 333:186–189

    Google Scholar 

  • Sarter M, Schneider HH (1988) High density of benzodiazepine binding sites in the substantia innominata of the rat. Pharmacol Biochem Behav 30:679–682

    Google Scholar 

  • Sarter M, Bodewitz G, Stephens DN (1988a) Attenuation of scopolamine-induced impairment of spontaneous alternation behavior by antagonist but not inverse agonist and agonist \-carbolines. Psychopharmacology 94:491–495

    Google Scholar 

  • Sarter M, Schneider HH, Stephens DN (1988b) Treatment strategies for senile dementia: antagonist \-carbolines. TINS 11:13–17

    Google Scholar 

  • Schopf 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

    Google Scholar 

  • Schwam E, Keim K, Cumin R, Gamzu E, Sepinwall J (1985) The effects of aniracetam on primate behavior and EEG. In: Olton DS, Gamzu E, Corkin S (eds) Memory dysfunctions: An integration of animal and human research from preclinical and clinical perspectives. Ann NY Acad Sci 444:482–484

  • Schweri M, Cain M, Cook J, Paul S, Skolnick P (1982) Blockade of 3-carbomethoxy-\-carboline-induced seizures by diazepam and the benzodiazepine antagonists Ro 15–1788 and CGS 8216. Pharmacol Biochem Behav 17:457–460

    Google Scholar 

  • Scollo-Lavizzari G (1983) First clinical investigation of the benzodiazepine antagonist Ro 15–1788 in comatose patients. Eur Neurol 22:7–11

    Google Scholar 

  • Shapiro SS, Wilk MB (1965) An analysis of variance test for normality (complete samples). Biometrika 52:591–611

    Google Scholar 

  • Skolnick P, Schweri MM, Paul SM, Martin JV, Wagner RL, Mendelson WB (1983) 3-Carboethoxy-\-carboline (B-CCE) elicits electroencephalographic seizures in rats: reversal by the benzodiazepine antagonist CGS 8216. Life Sci 32:2439–2445

    Google Scholar 

  • Snyder SH, Katims J, Annau Z, Bruns R, Daly J (1981) Adenosine receptors and behavioral actions of methylxanthines. Proc Natl Acad Sci USA 78:3260–3264

    Google Scholar 

  • Spignoli G, Pedata F, Giovannelli L, Banfi S, Moroni F, Pepeu G (1986) Effect of oxiracetam and piracetam on central cholinergic mechanisms and active avoidance acquisition. Clin Neuropharmacol 9 (suppl 3):39–47

    Google Scholar 

  • Squires R, Braestrup C (1977) Benzodiazepine receptors in rat brain. Nature 266:732–734

    Google Scholar 

  • Stewart DJ, Macfabe DF, Vanderwolf CH (1984) Cholinergic activation of the electrocorticogram: role of the substantia innominata and effects of atropine and quinuclidinyl benzilate. Brain Res 322:219–232

    Google Scholar 

  • Stumpf C (1965) Drug action on the electrical activity of the hippocampus. Int Rev Neurobiol 8:77–138

    Google Scholar 

  • Stutzmann JM, Böhme GA, Cochon N, Roux M, Blanchard JC (1987) Proconflict and electrocorticographic effects of drugs modulating GABAergic neurotransmission. Psychopharmacology 91:74–79

    Google Scholar 

  • Valin A, Dodd RH, Liston DR, Potier P, Rossier J (1982) Methyl\-carboline-induced convulsions are antagonized by Ro 15–1788 and by propyl-\-carboline. Eur J Pharmacol 85:95–97

    Google Scholar 

  • Vanderwolf CH (1975) Neocortical and hippocampal activation in relation to behavior: effects of atropine, eserine, phenothiazines and amphetamine. J Comp Physiol Psychol 88:300–323

    Google Scholar 

  • Venault P, Chapouthier G, Prado de Carvalho L, Simiand J, Morre M, Dodd RH, Rossier J (1986) Benzodiazepine impairs and \-carboline enhances performance in learning and memory tasks. Nature 321:864–866

    Google Scholar 

  • Yamaguchi Y, Yoshii H, Miyamoto K, Itoigawa N (1967) A study on the invasive hippocampal θ-waves to the cortex. Progr Brain Res 27:281–292

    Google Scholar 

  • Ziegler G, Ludwig L, Fritz G (1985) Reversal of slow-wave sleep by benzodiazepine antagonist Ro 15–1788. The Lancet II: 510

    Google Scholar 

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  1. Kathleen Bizière

    Present address: Department of Clinical Pharmacology, Hoffmann-La Roche Ltd, CH-4002, Basel, Switzerland

Authors and Affiliations

  1. Department of Neuropsychiatry, Sanofi Recherche, Rue du Prof. J. Blayac, F-34082, Montpellier Cedex, France

    Vincent Santucci, Michèle Fournier, Paul Worms & Kathleen Bizière

  2. Department of Neuropsychiatry, Sanofi Recherche, 195, Route d'Espagne, F-31000, Toulouse, France

    Peter Keane

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Santucci, V., Fournier, M., Worms, P. et al. Cerebral-activating (EEG) properties of two inverse agonists and of an antagonist at the benzodiazepine receptor in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 340, 93–100 (1989). https://doi.org/10.1007/BF00169213

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