Abstract
The peripheral BDZ receptor ligand Ro 5-4864 was administered to rabbits in doses ranging from 0.2 to 7 mg/kg IV. Changes in electrocortical activity appeared within 1 min after administration, characterized by trains of slow waves in the posterior sensorimotor and optic cortices (0.6–2 mg/kg) and by grand mal seizures (2–10 mg/kg). The low doses also induced alterations in the basic rhythms both of the hippocampus (reduced amplitude and spike-like waves) and of the nucleus ventralis of thalamus (trains of slow waves), not associated with observable behavioural changes. The paroxysmal EEG activity observed at higher doses of the drug was first recorded in the cortical areas and then spread to the subcortical structures. No change in electrical activity could be observed in the spinal cord. The paroxysmal activity was associated with tonic-clonic convulsions and scialorrea.
The EEG and behavioural manifestations were inhibited by administration of Ro 15-1788. This drug at doses of 0.6 and 6 mg/kg antagonized the effects of Ro 5-4864 at doses of 0.6–5 mg/kg and 6–7 mg/kg, respectively. This effect began 1–3 min after administration of the antagonist, and led to EEG synchronization.
These data suggest that in rabbits the convulsant effect of Ro 5-4864 is due to interference of the drug at the GABA-BDZ-picrotoxin receptor oligomeric complex. Such an effect seems to be mediated at least in part by central BDZ receptors.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bovet D, Longo VG (1961) Localization of the action of convulsant substances. Correlation between electroencephalographic and biochemical findings. The regional chemistry, physiology and pharmacology of the nervous system. In: Proc. 4th International Neurochemical Symposium, Pergamon Press, London, pp 456–464
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
Daviest LP, Huston V (1983) Peripheral benzodiazepine binding sites in heart and their interaction with dipyridamole. Eur J Pharmacol 73:209–211
Del Zompo M, Bocchetta A, Corsini GV, Tallman JF, Gessa GL (1983) Properties of benzodiazepine binding sites in peripheral tissues. Adv Biochem Psychopharmacol 38:239–248
File SE, Lister RG, Nutt DJ (1982) The anxiogenic action of benzodiazepine antagonists. Neuropharmacology 21:1033–1037
File SE, Pellow S (1983) Ro 5–4864, a ligand for benzodiazepine micromolar and peripheral binding sites: antagonism and enhancement of behavioural effects. Psychopharmacology 80:166–170
File SE, Green AR, Nutt DJ, Vincent ND (1984) On the convulsant action of Ro 5–4864 and the existence of a micromolar benzodiazepine binding site in rat brain. Psychopharmacology 82:199–202
File SE, Pellow S (1985) The anxiogenic action of Ro 5–4864 in the social interaction test: effects of chlordiazepoxide, Ro 15–1788 and CGS 8216. Naunyn Schmiedeberg's Arch Pharmacol 328:225–228
Florio V, Longo VG (1972) Electroencephalographic effects of bicuculline. Physiol Behav 9:283–285
Hunkeler W, Möhler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1983) Selective antagonists of benzodiazepine. Nature 290:514–516
Longo VG (1962) Electroencephalographic atlas for pharmacological research: effects of drugs on the electrical activity of the rabbit brain. Elsevier, Amsterdam
Longo VG, Massotti M, Sagratella S (1983) Convulsant drugs and changes in the electrical activity of the brain: an investigation of the effects of opioids on chemoconvulsions. In: C. Nisticò, R. Di Perri and H. Mainardi (eds) Epilepsy: An update on research and therapy, Alan Liss Inc., New York, pp 121–127
Marangos PJ, Patel J, Boulenger JP, Clark-Rosenberg R (1982) Characterization of peripheral-type benzodiazepine binding sites in brain using 3H-Ro 5–4864. Mol Pharmacol 22:26–32
Massotti M (1984) Neuropharmacology of agonist and antagonist drugs acting at GABA-benzodiazepine-Cl- channel complex. Clin Neuropharmacol 7 (suppl 1):894–895
Massotti M (1985) Electroencephalographic investigation in rabbits of drugs acting at GABA-benzodiazepine-barbiturte/picrotoxin receptor complex. Pharmacol Biochem Behav 23:661–670
Massotti M, Lucantoni D, Caporali MG, Mele L, Gatta F (1985) Supraspinal convulsions induced by inverse benzodiazepine agonists in rabbits. J Pharmacol Exp Ther 234:274–279
Mizoule J, Gauthier A, Uzan A, Renault C, Dubroeucq MC, Guérémy C, Le Fur G (1985) Opposite effects of two ligands for peripheral type benzodiazepine binding sites, PK 11195 and Ro 5–4864, in a conflict situation in the rat. Life Sci 36:1059–1068
Möhler H, Richards JG (1983) Receptors for anxiolytic drugs. In: J Malick, S Enna, H Yamamura (eds) Anxiolytic: Neurochemical, behavioral and clinical perspectives. Raven Press, New York, pp 15–28
Pellow S, File SE (1984a) Multiple sites of action for anxiogenic drugs: behavioural, electrophysiological and biochemical correlations. Psychopharmacology 83:304–314
Pellow S, File SE (1984b) Behavioural actions of Ro 5–4864: a peripheral-type benzodiazepine? Life Sci 35:229–240
Pieri L, Polc P, Bonetti EP, Burkard W, Cumin R, Haefely W (1983) Some pharmacological effects of Ro 5–4864, a specific ligand of the peripheral type benzodiazepine binding sites. Naunyn Schmiedeberg's Arch Pharmacol 322:R95
Polc P, Schaffner R (1983) Electrophysiological effects of the peripheral-type benzodiazepine receptor ligand Ro 5–4864 in cat spinal cord and rat hippocampus. Neurosci Lett Suppl 14:S 288
Richards JC, Möhler H, Haefely W (1982) Benzodiazepine binding sites: receptors or acceptors? TIPS 3:233–235
Richards JG, Möhler H (1984) Benzodiazepine receptors. Neuropharmacology 23:233–242
Sagratella S, Massotti M (1982) Convulsant and anticonvulsant effects of opioids: relationship to GABA-mediated transmission. Neuropharmacology 21:991–1000
Schoemaker H, Bliss IM, Yamamura HI (1981) Specific high affinity saturable binding of 3H-Ro 5–4864 to benzodiazepine binding sites in rat cerebral cortex. Eur J Pharmacol 71:173–175
Schoemaker HI, Morelli M, Desmuk PD, Yamamura HT (1982) 3H-Ro 5–4864 benzodiazepine binding in kainate lesioned striatum and Huntington's diseased basal ganglia. Brain Res 248:396–401
Schoemaker H, Bales RG, Horst WD, Yamamura HI (1983) Specific high-affinity binding sites for 3H-Ro 5–4864 in rat brain and kidney. J Pharmacol Exp Ther 225:61–69
Skerrit JH, Werz MA, McLean MJ, MacDonald RL (1984) Diazepam and its anomalous p-chloro-derivative Ro 5–4864: comparative effects on mouse neurons in cell culture. Brain Res 310:99–105
Ticku MK, Ramanjaneyulu R (1984) Ro 5–4864 inhibits the binding of 35S-t-butylbiciclo-phosphorothionate to rat brain membranes. Life Sci 34:631–638
Weissman BA, Cott J, Paul SM, Skolnick P (1983) Ro 5–4864: a potent benzodiazepine convulsant. Eur J Pharmacol 90:149–150
Weissman BA, Cott J, Hammer D, Paul S, Skolnick P (1984) Electrophysiological and pharmacological actions of the convulsant benzodiazepine Ro 5–4864. Eur J Pharmacol 97:257–263
Zbinden G, Randall LD (1967) Pharmacology of benzodiazepines: laboratory and clinical correlations. Adv Pharmacol 5:213–292
Author information
Authors and Affiliations
Additional information
Offprint requests to: M. Massotti
Rights and permissions
About this article
Cite this article
Massotti, M., Lucantoni, D. The peripheral benzodiazepine receptor ligand Ro 5-4864 induces supraspinal convulsions in rabbits. Reversal by the central benzodiazepine antagonist Ro 15-1788. Psychopharmacology 88, 336–340 (1986). https://doi.org/10.1007/BF00180835
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00180835