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Withdrawal precipitation by benzodiazepine receptor antagonists in dogs chronically treated with diazepam or the novel anxiolytic and anticonvulsant β-carboline abecarnil

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Summary

The effects of the benzodiazepine (BZ) receptor antagonists flumazenil (Ro 15-1788) and the β-carboline ZK 93426 were compared in dogs before and after chronic treatment with diazepam or the novel BZ receptor ligand abecarnil (ZK 112119). Abecarnil, β-carboline, is thought to act as partial (low efficacy) and/or subtype selective agonist at central BZ receptors. Diazepam and abecarnil were administered at doses which, based on previous experiments on anticonvulsant activity, resulted in about equieffective drug concentrations during treatment. In dogs treated with diazepam, 6 mg/kg/day p.o., for 2 weeks, severe abstinence symptoms, including seizures, were precipitated in all animals by i. v. infusion of the BZ receptor antagonists, differences being found in the type of symptoms caused by flumazenil and ZK 93426. In dogs treated with abecarnil, 4 mg/kg/d s. c., for 6 weeks, only relatively mild abstinence symptoms were precipitated by infusion of flumazenil or ZK 93426, although pharmacologically active plasma concentrations of abecarnil had been maintained throughout the period of treatment. This suggests that BZ receptor ligands which act as partial and/or selective agonists might be more favourable than traditional agonists, such as diazepam, regarding the induction of physical dependence.

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References

  • Ballenger JC, Mcdonald S, Noyes R, Rickels K, Sussman N, Woods S, Patin J, Singer J (1991) The first double-blind, placebo-controlled trial of a partial benzodiazepine agonist abecanil (ZK-112–119) in generalized anxiety disorder. Psychopharmacol Bull 27:171–179

    Google Scholar 

  • Corda MG, Costa E, Guidotti A (1982) Specific proconvulsant action of an imidazobenzodiazepine (Ro 15–1788) on isoniazid convulsions. Neuropharmacology 21:91–94

    Google Scholar 

  • Costa E (1990) “Spare receptors” and “partial agonists” — Romantic terms to explain a pharmacology deriving from the structural diversity of GABAA receptors. In: Biggio G, Costa E(eds) GABA and benzodiazepine receptor subtypes. Raven, New York, pp 221–230

    Google Scholar 

  • Cumin R, Benetti EP, Scherschlicht R, Haefely WE (1982) Use of the specific benzodiazepine antagonist, Ro-15–1788, in studies of physiological dependence on benzodiazepines. Experientia 38:833–834

    Google Scholar 

  • De Deyn PP, Macdonald RL (1987) CGS 9896 and ZK 91296, but not CGS 8216 and Ro 15–1788, are pure benzodiazepine antagonists on mouse neurons in culture. J Pharmacol Exp Ther 242:48–55

    Google Scholar 

  • Duka T, Schutt B, Dorow R, MaDonald S, Krause W, Fichte K (1989) ZK 112119, a β-carboline anxiolytic: Phase I single and multiple dose studies to establish safety, tolerability and drug effects. Eur J Clin Pharmacol 36 [Suppl]:A48

    Google Scholar 

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

    Google Scholar 

  • Frey H-H, Löscher W (1982) Anticonvulsant potency of unmetabolized diazepam. Pharmacology 25:154–159

    Google Scholar 

  • Frey H-H, Philippin H-P, Scheuler W (1984) Development of tolerance to the anticonvulsant effect of diazepam in dogs. Eur J Pharmacol 104:27–38

    Google Scholar 

  • Giorgi O, Corda MG, Fernandez A, Biggio G (1988) The abstinence syndrome in diazepam-dependent cats is precipitated by Ro 15–1788 and Ro 15–4513 but not by the benzodiazepine receptor antagonist ZK 93426. Neurosci Lett 88:206–210

    Google Scholar 

  • Giorgi O, Corda MG, Fernandez A, Biggio G (1989) The β-carboline derivatives ZK 93426 and FG 7142 fail to precipitate abstinence signs in diazepam-dependent cats. Pharmacol Biochem Behav 32:671–675

    Google Scholar 

  • Gobbi M, Barone D, Mennini T, Garattini S (1987) Diazepam and desmethyldiazepam differ in their affinities and efficacies at “central” and “peripheral” benzodiazepine receptors. J Pharm Pharmacol 39:388–391

    Google Scholar 

  • Guentert TW (1984) Pharmacokinetics of benzodiazepines and their metabolites. In: Bridges JW, Chasseaud LF (eds) Progress in drug metabolism, vol 8. Taylor and Francis, London Philadelphia, pp 241–386

    Google Scholar 

  • Haefely W (1985) Pharmacology of benzodiazepine antagonists. Pharmacopsychiatry 18:163–166

    Google Scholar 

  • Haefely W, Martin JR, Schoch P (1990) Novel anxiolytics that act as partial agonists at benzodiazepine receptors. Trends Pharmacol Sci 11:452–456.

    Google Scholar 

  • Haigh JRM, Feely M (1988) Tolerance to the anticonvulsant effect of benzodiazepines. Trends Pharmacol Sci 9:361–391

    Google Scholar 

  • 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 93426 as a benzodiazepine receptor antagonist. Psychopharmacology 83:249–256

    Google Scholar 

  • Krause W, Mengel H, Nordholm L (1989) Determination of β-carboline derivatives in biological samples by high-performance liquid chromatography with fluorescence detection. J Pharm Sci 78:622–626

    Google Scholar 

  • Krause W, Schutt B, Duka T (1990) Pharmacokinetics and acute toleration of the β-carboline derivative abecarnil in man. Arzneim-Forsch (Drug Res) 40:529–532

    Google Scholar 

  • Little HJ, Nutt DJ, Taylor SC (1986) Does chronic benzodiazepine administration cause a “withdrawal shift” across the whole benzodiazepine ligand spectrum? Br J Pharmacol 89 [Suppl]:796P

  • Löscher W (1983) Alterations in CSF GABA levels and seizure susceptibility developing during repeated administration of pentetrazole in dogs. Effects of γ-acetylenic GABA, valproic acid and phenobarbital. Neurochem Int 5:405–412

    Google Scholar 

  • Löscher W, Frey H-H (1981) Pharmacokinetics of diazepam in the dog. Arch Int Pharmacodyn Ther 254:180–196

    Google Scholar 

  • Löscher W, Schneider H, Kehr W (1985) Evaluation of different β-carbolines in Mongolian gerbils with reflex epilepsy. Eur J Pharmacol 114:261–266

    Google Scholar 

  • Löscher W, Honack D, Hashem A (1987) Anticonvulsant efficacy of clonazepam and the β-carboline ZK 93423 during chronic treatment in amygdala-kindled rats. Eur J Pharmacol 143: 403–414

    Google Scholar 

  • Löscher W, Honack D, Faßbender CP (1989) Physical dependence on diazepam in the dog: precipitation of different abstinence syndromes by the benzodiazepine receptor antagonists Ro 15–1788 and ZK 93426. Br J Pharmacol 97:843–852

    Google Scholar 

  • Löscher W, Hönack D, Scherkl R, Hashem A, Frey H-H (1990) Pharmacokinetics, anticonvulsant efficacy and adverse effects of the β-carboline abecarnil, a novel ligand for benzodiazepine receptors, after acute and chronic administration in dogs. J Pharmacol Exp Ther 255:541–548

    Google Scholar 

  • Lukas SE, Griffiths RR (1984) Precipitated diazepam withdrawal in baboons: effect of dose and duration of diazepam exposure. Eur J Pharmacol 100:163–171

    Google Scholar 

  • McNicholas LF, Martin WR, Cherian S (1983) Physical dependence on diazepam and lorazepam in the dog. J Pharmacol Exp Ther 226:783–789

    Google Scholar 

  • McNicholas LF, Martin WR, Pruitt TA (1985) N-Desmethyl-diazepam physical dependence in dogs. J Pharmacol Exp Ther 235:368–376

    Google Scholar 

  • Owen RT, Tyrer P (1983) Benzodiazepine dependence: a review of the evidence. Drugs 25:385–398

    Google Scholar 

  • Petersen EN, Jensen LH (1987) Chronic treatment with lorazepam and FG 7142 may change the effects of benzodiazepine receptor agonists, antagonists and inverse agonists by different mechanisms. Eur J Pharmacol 133:309–317

    Google Scholar 

  • Scherkl R, Frey H-H (1986) Physical dependence on clonazepam in dogs. Pharmacology 32:18–24

    Google Scholar 

  • Scherkl R, Scheuler W, Frey H-H (1985) Anticonvulsant effect of clonazepam in the dog: development of tolerance and physical dependence. Arch Int Pharmacodyn Thér 278:249–260

    Google Scholar 

  • Scherkl R, Kurudi D, Frey H-H (1989) Clorazepate in dogs: tolerance to the anticonvulsant effect and signs of physical dependence. Epilepsy Res 3:144–150

    Google Scholar 

  • Stephens DN, Schneider HH, Kehr W, Andrews JS, Rettig K-J, Turski L, Schmiechen R, Turner JD, Jensen LH, Petersen EN, Honoré T, Bondo Hansen J (1990) Abecarnil, a metabolically stable, anxioselective β-carboline acting at benzodiazepine receptors. J Pharmacol Exp Ther 253:334–343

    Google Scholar 

  • Stephens DN, Schneider HH, Turski L, Hillmann M, Huba R, Turner JD (1991) Abecarnil: A β-carboline anxiolytic showing a selective action at central benzodiazepine receptors. Soc Neurosci Abstr 17:1342

    Google Scholar 

  • Turski L, Stephens DN, Jensen LH, Petersen EN, Meldrum BS, Patel S, Bondo Hansen J, Löscher W, Schneider HH, Schmiechen R (1990) Anticonvulsant action of the β-carboline abecarnil — Studies in rodents and baboon, Papio papio. J Pharmacol Exp Ther 253:344–352

    Google Scholar 

  • Wilson MA, Gallager DW (1988) Ro 15–1788-induced seizures in rats continually exposed to diazepam for prolonged periods. Epilepsy Res 2:14–19

    Google Scholar 

  • Wilson JI, Feely M, Gent JP (1989) Apparent separation of benzodiazepine tolerance and dependence: flumazenil does not abolish the withdrawal effect. Br J Pharmaco196: 676P

  • Woods JH, Katz JL, Winger G (1987) Abuse liability of benzodiazepines. Pharmacol Rev 39:251–419

    Google Scholar 

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Löscher, W., Hönack, D. Withdrawal precipitation by benzodiazepine receptor antagonists in dogs chronically treated with diazepam or the novel anxiolytic and anticonvulsant β-carboline abecarnil. Naunyn-Schmiedeberg's Arch Pharmacol 345, 452–460 (1992). https://doi.org/10.1007/BF00176624

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