Abstract
Proconflict and electrocorticographic effects of drugs acting on the benzodiazepine (BDZ)/GABA/chloride-ionophore receptor complex were studied in rats in an attempt to correlate their anxiogenic and epileptogenic activities. Evidence for proconflict activity was assessed by means of an operant conflict procedure based on the simultaneous reward and punishment of a conditioned task, while epileptogenic properties were assessed by monitoring the electrocorticogram (ECoG) of free-moving rats. Pentylenetetrazole and picrotoxin, which act through a site on the chloride channel, and the benzodiazepine (BDZ) inverse agonist FG 7142 showed epileptogenic alterations in the ECoG at doses, respectively, 8, 2 and 3 times higher than those eliciting a significant proconflict effect. For the partial inverse agonist CGS 8216, a ratio of about 60 was found while the BDZ antagonist Ro 15-1788 showed neither epileptogenic nor proconflict activity, except at the highest tested dose for the latter effect (40 mg·kg−1 PO). Inhibition of GABA transmission may mediate both anxiogenic and epileptogenic actions, and a link between these properties may exist as a continuous spectrum of negative intrinsic efficacy at the central BDZ/GABA/chloride-ionophore receptor complex.
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References
Braestrup C, Albrechtsen R, Squires RF (1977) High densities of benzodiazepine receptors in human cortical areas. Nature 269:702–704
Costa E, Guidotti A (1979) Molecular mechanisms in the receptor action of benzodiazepines. Ann Rev Pharmacol Toxicol 19:531–545
Dorow R, Horowski R, Paschelke G, Amin M, Braestrup C (1983) Severe anxiety induced by FG 7142, a β-carboline ligand for benzodiazepine receptors. Lancet II:98–99
File SE, Lister RG (1984) Do the reductions in social interaction produced by picrotoxin and pentylenetetrazole indicate anxiogenic actions. Neuropharmacology 23:793–796
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
File SE, Lister RG, Nutt DJ (1982) The anxiogenic actions of benzodiazepine antagonists. Neuropharmacology 21:1033–1037
Hunkeler W, Möhler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290:514–516
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
Kehr W, Stephens DN (1984) Further evidence that central benzodiazepine receptor ligands may exhibit anxiogenic properties. Br J Pharmacol 81:42P
Lal H, Emmett-Oglesby MW (1983) Behavioral analogues of anxiety: animal models. Neuropharmacology 22:1423–1444
Massoti M (1985) Electroencephalographic investigations in rabbits of drugs acting at GABA-benzodiazepine-barbiturate/picrotoxin receptor complex. Pharmacol Biochem Behav 23:661–670
Möhler H, Okada T (1977) Benzodiazepine receptors: demonstration in the CNS. Science 198:849–851
Möhler H, Okada T (1978) Biochemical identification of the site of action of benzodiazepine in human brain by3H-diazepam binding. Life Sci 22:985–996
Olsen RW (1981) GABA-benzodiazepine-barbiturate receptor interactions. J Neurochem 37:1–13
Ongini E (1983) Behavioral and EEG effects of benzodiazepines and their antagonists in the cat. In: Biggio G, Costa E (eds) Benzodiazepine recognition site ligands: biochemistry and pharmacology. Raven, New York, pp 211–225
Petersen EN, Jensen LH (1984) Proconflict effect of benzodiazepine receptor inverse agonists and other inhibitors of GABA function. Eur J Pharmacol 103:91–97
Petersen EN, Paschelke G, Kehr W, Nielsen M, Braestrup C (1982) Does the reversal of the anticonflict effect of phenobarbital by β-CCE and FC 7142 indicate benzodiazepine mediated anxiogenic properties. Eur J Pharmacol 82:217–221
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
Pieri L, Biry P (1985) Isoniazid-induced convulsions in rats: effects of Ro 15-1788 and β-CCE. Eur J Pharmacol 112:355–362
Polc 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 tranquilisers, β-carbolines and phenobarbital. Naunyn Schmiedebergs. Arch Pharmacol 321:260–264
Prado de Carvalho L, Greksch G, Chapouthier G, Rossier J (1983) Anxiogenic and non-anxiogenic benzodiazepine antagonists. Nature 301:64–66
Ramanjaneyulu R, Ticku MK (1984) Interactions of pentametylenetetrazole and tetrazole analogues with the picrotoxinin site of the benzodiazepine-GABA-receptor ionophore complex. Eur J Pharmacol 98:337–345
Rodin E (1958) Metrazol tolerance in “normal” volunteer population. Electroencephalogr Clin Neurophysiol 10:433–446
Rossier J, Dodd RH, Feldblum S, Valin A, Prado de Carvalho L, Potier P, Naquet R (1983) Methylamide β-carboline (FG 7142), an anxiogenic benzodiazepine antagonist, is also a proconvulsant. Lancet I:77–78
Squires RF, Braestrup C (1977) Benzodiazepine receptors in rat brain. Nature 266:732–734
Squires RF, Saederup E, Crawley JN, Skolnick P, Paul SM (1984) Convulsant potencies of tetrazoles are highly correlated with actions on GABA/benzodiazepine/picrotoxin receptor complexes in brain. Life Sci 35:1439–1444
Stephens DN, Kehr W (1985) β-carboline can enhance or antagonize the effects of punishment in mice. Psychopharmacology 85:143–147
Williams M (1984) Molecular aspects of the action of benzodiazepine and non-benzodiazepine anxiolytics: a hypothetical allosteric model of the benzodiazepine receptor complex. Prog Neuropsychopharmacol Biol Psychiatry 8:209–247
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Stutzmann, JM., Böhme, G.A., Cochon, M. et al. Proconflict and electrocorticographic effects of drugs modulating GABAergic neurotransmission. Psychopharmacologia 91, 74–79 (1987). https://doi.org/10.1007/BF00690930
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DOI: https://doi.org/10.1007/BF00690930