Abstract
In neurological and behavioral studies in mice, rats, dogs and squirrel monkeys, the imidazobenzodiazepinone Ro 15-1788 acted as a potent benzodiazepine antagonist. The antagonistic activity was both preventive and curative and seen at doses at which no intrinsic effects were detected. It was highly selective in that it acted against CNS effects induced by benzodiazepines but not against those produced by other depressants, such as phenobarbitone, meprobamate, ethanol, and valproate. The onset of action was rapid even after oral administration. Depending on the animal species studied, the antagonistic effects lasted from a few hours to 1 day. The acute and subacute toxicity of Ro 15-1788 was found to be very low. Benzodiazepine-like effects were not seen.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Beglinger R, Hamza B, Heizmann P, Kyburz E, Rehm WF (1982) Untersuchungen zur Anwendung und Antagonisierung von Benzodiazepinen beim Rind. DTW 89:137–142
Boissier JR, Simon P (1960) L'utilisation du test de la traction (Test de Julou-Courvoisier) pour l'étude des psycholeptiques. Thérapie 15:1170–1174
Bosmann HB, Case R, DiStefano P (1977) Diazepam receptor characterization: Specific binding of a benzodiazepine to macromolecules in various areas of rat brain. FEBS Lett 82:368–372
Braestrup C, Squires RF (1977) Specific benzodiazepine receptors in rat brain characterized by high-affinity 3H-diazepam binding. Proc Natl Acad Sci USA 74:3805–3809
Choi DW, Farb DH, Fischbach GD (1981) Chlordiazepoxide selectively potentiates GABA conductance of spinal cord and sensory neurons in cell culture. J Neurophysiol 45:621–631
Cook L, Weidley E (1957) Behavioral effects of some psychopharmacological agents. Ann NY Acad Sci 66:740–752
Cook L, Davidson AB (1973) Effects of behaviourally active drugs in a conflict punishment procedure in rats. In: Garattini S, Mussini E, Randall LO (eds) Benzodiazepines. Raven, New York, pp 327–345
Costa E, Guidotti A, Mao CC (1975) Evidence for the involvement of GABA in the action of benzodiazepines: studies on rat cerebellum. In: Costa E, Greengard P (eds) Mechanism of action of benzodiazepines. Raven, New York, pp. 113–130
Costa E, Guidotti A, Toffano G (1978) Molecular mechanism mediating the action of diazepam on GABA receptors. Br J Psychiatry 133:239–248
Costa E, Corda MG, Epstein B, Forchetti C, Guidotti A (1982a) GABA/benzodiazepine interactions. In: Costa E, Haefely W, Amrein R, Ward J (eds) Benzodiazepines: Molecular biology to clinical practice. Raven, New York (in press)
Costa E, Haefely W, Amrein R, Ward J (1982b) Benzodiazepines: Molecular biology to clinical practice. Raven, New York (in press)
Courvoisier S (1956) Pharmacodynamic basis for the use of chlorpromazine in psychiatry. J Clin Exp Psychopathol 17:25–37
Cumin R, Bonetti EP, Scherschlicht R, Haefely WE (1982) Use of the specific benzodiazepine antagonist Ro 15-1788 in studies of physiological dependence on benzodiazepines. Experientia (in press)
Darragh A, Lambe R, Scully M, Brick I, O'Boyle C, Downie WW (1981) Investigation in man of the efficacy on a benzodiazepine antagonist, Ro 15-1788. Lancet II:8–10
Duka T, Cumin R, Haefely W, Herz A (1981) Naloxone blocks the effect of diazepam and meprobamate on conflict behaviour in rats. Pharmacol Biochem Behav 15:115–117
Geller I, Seifter J (1960) The effects of meprobamate, barbiturates, d-amphetamine and promazine on experimentally induced conflict in the rat. Psychopharmacologia 1:482–492
Haefely W (1978) Behavioural and neuropharmacological aspects of drugs used in anxiety and related states. In: Lipton MA, DiMascia A, Killam KF (eds) Psychopharmacology: A generation of progress. Raven, New York, pp 1359–1374
Haefely W, Kulcsar A, Möhler H, Pieri L, Polc P, Schaffner R (1975) Possible involvement of GABA in the central actions of benzodiazepines. In: Costa E, Greengard P (eds) Mechanism of action of benzodiazepines. Raven, New York, pp 357–375
Haefely W, Pieri L, Pole P, Schaffner R (1981) General pharmacology and neuropharmacology of benzodiazepine derivatives. In: Hoffmeister F, Stille G (eds) Handbook of experimental pharmacology, vol 55. Springer, Berlin Heidelberg New York, pp 13–262
Haefely W, Pole P, Pieri L, Schaffner R, Laurent JP (1982) Neuropharmacology of benzodiazepines: Synaptic mechanisms and neural basis of action. In: Costa E, Haefely W, Amrein R, Ward J (eds) Benzodiazepines: Molecular biology to clinical paractice. Raven, New York (in press)
Heise GA, Boff E (1962) Continuous avoidance as a baseline for measuring behavioural effects of drugs. Psychopharmacologia 3:264–282
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
Irwin S (1968) Comprehensive observational assessment: Ia. A systematic quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia 13:222–257
Lotz W (1982) Benzodiazepine antagonist Ro 15-1788 counteracts the prolactin-lowering effects of other benzodiazepines in rats. Neuroendocrinol 35:32–36
Möhler H, Okada T (1977) Benzodiazepine receptor: Demonstration in the central nervous system. Science 198:849–851
Möhler H, Richards JG (1981) Agonist and antagonist benzodiazepine receptor interaction in vitro. Nature 294:763–765
Möhler H, Burkard WP, Keller HH, Richards JG, Haefely W (1981) Benzodiaepine antagonist Ro 15-1788: Binding characteristics and interaction with drug-induced changes in dopamine turnover and cerebellar cGMP levels. J Neurochem 37:714–722
Olsen RW (1981) GABA-benzodiazepine-barbiturate receptor interaction. J Neurochem 37:1–13
Pieri L, Schaffner R, Scherschlicht R, Pole P, Sepinwall J, Davidson A, Möhler H, Cumin R, DaPrada M, Burkard WP, Keller HH, Müller PKM, Gerold M, Pieri M, Cook L, Haefely W (1981) Pharmacology of midazolam. Drug Res 31:2180–2201
Polc P, Laurent JP, Scherschlicht R, Haefely W (1981) Electrophysiological studies on the specific benzodiazepine antagonist Ro 15-1788. Naunyn-Schmiedeberg's Arch Pharmacol 316:317–325
Shay H, Komarov SA, Fels SS, Meranze D, Gruenstein M, Siplet H (1945) A simple method for the uniform production of gastric ulceration in the rat. Gastroenterology 5:43–61
Study RE, Barker JL (1981) Diazepam and (-)pentobarbital: Fluctuation analysis reveals different mechanisms for potentiation of GABA responses in cultured central neurons. Proc Natl Acad Sci USA 78:7180–7184
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bonetti, E.P., Pieri, L., Cumin, R. et al. Benzodiazepine antagonist Ro 15-1788: Neurological and behavioral effects. Psychopharmacology 78, 8–18 (1982). https://doi.org/10.1007/BF00470579
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00470579