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Effect of convulsant and anticonvulsant agents on level and metabolism of γ-aminobutyric acid in mouse brain

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Summary

  1. 1.

    The effect of the convulsant agents pentetrazole, picrotoxin, bicuculline, strychnine and isoniazid on the central level of \gg-aminobutyric acid (GABA) and the activity of the enzymes glutamate decarboxylase (GAD) and GABA-\ga-oxoglutarate aminotransferase (GABA-T) from mice brain was studied in vivo and in vitro.

    In vivo, convulsant doses of picrotoxin and isoniazid lowered the level of GABA and the activity of GAD, whereas strychnine and bicuculline had no such effect. Pentetrazole inhibited GAD, but did not alter the GABA content.

    In vitro, all convulsants, except bicuculline, inhibited the activity of GAD; however, the concentrations of strychnine were far beyond the range that is reached in vivo by convulsant doses. Only isoniazid inhibited the activity of GABA-T in vivo as well as in vitro.

  2. 2.

    Phenobarbital, ethosuximide and trimethadione were about equally active in preventing convulsions induced by strychnine and picrotoxin, whereas diazepam was 9 times, and sodium valproate 3.5 times more active against convulsions elicited by picrotoxin. Phenytoin up to 100 mg/kg was ineffective against all chemoconvulsants.

  3. 3.

    Diazepam, sodium valproate, ethosuximide and trimethadione antagonized the inhibition of GAD and the decrease in GABA concentrations caused by isoniazid. Phenobarbital and phenytoin prevented the decrease of GABA but did not reverse the inhibition of GAD.

  4. 4.

    The results suggest a role played by the transmitter pool of GABA in the convulsant action of chemoconvulsants and in the anticonvulsant effect of antiepileptics clinically used in petit mal epilepsy.

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References

  • Balázs, R., Machiyama, Y., Hammond, B. J., Julian, T., Richter, D.: The operation of the γ-aminobutyrate bypath of the tricarboxyclic acid cycle in brain tissue in vitro. Biochem. J. 116, 445–467 (1970)

    Google Scholar 

  • Bruggencate, G., ten, Engberg, J.: Iontophoretic studies in Deiter's nucleus of the inhibitory actions of GABA and related amino acids and the interactions of strychnine and picrotoxine. Brain Res. 25, 431–448 (1971)

    Google Scholar 

  • Costa, E., Guidotti, A., Mao, C. C., Suria, A.: New concepts on the mechanism of action of benzodiazepines. Life Sci. 17, 167–186 (1975)

    Google Scholar 

  • Curtis, D. R., Duggan, A. W., Felix, D., Johnston, G. A. R.: GABA, bicuculline and central inhibition. Nature (Lond.) 226, 1222–1224 (1970)

    Google Scholar 

  • Dray, A., Straughan, D. W.: Benzodiazepines: GABA and glycine receptors on single neurons in the rat medulla. J. Pharm. Pharmacol. 28, 314–315 (1976)

    Google Scholar 

  • Frey, H.-H., Löscher, W.: Di-n-propylacetic acid — profile of anticonvulsant activity in mice. Arzneimittel-Forsch. (Drug Res.) 26, 299–301 (1976)

    Google Scholar 

  • Godin, Y., Heiner, L., Mark, J., Mandel, P.: Effects of di-n-propylacetate, an anticonvulsive compound, on GABA metabolism. J. Neurochem. 16, 869–873 (1969)

    Google Scholar 

  • Hill, R. G., Simmonds, M. A.: A method for comparing the potencies of γ-aminobutyric acid antagonists on single cortical neurons using microiontophoretic techniques. Brit. J. Pharmacol. 48, 1–11 (1973)

    Google Scholar 

  • Hill, R. G., Simmonds, M. A., Straughan, D. W.: A comparative study of some convulsant substances as γ-aminobutyric acid antagonists in the feline cerebral cortex. Brit. J. Pharmacol. 49, 37–51 (1973)

    Google Scholar 

  • Hill, R. G., Simmonds, M. A., Straughan, D. W.: Convulsant substances as antagonists of GABA and presynaptic inhibition in the cuneate nucleus. Brit. J. Pharmacol. 52, 117P (1974)

  • Horvath, A., Orrego, F., McKennis, H.: Factors controlling the metabolism of γ-aminobutyric acid. J. Pharmacol. exp. Ther. 134, 222–226 (1961)

    Google Scholar 

  • Killam, K. F., Bain, J. A.: Convulsant hydrazides. I. In vitro and in vivo inhibition of vitamin B6 enzymes by convulsant hydrazides. J. Pharmacol. exp. Ther. 119, 255–262 (1957)

    Google Scholar 

  • Litchfield, J. T., Wilcoxon, F.: A simplified method of evaluating dose-effect experiments. J. Pharmacol. exp. Ther. 96, 99–113 (1949)

    Google Scholar 

  • Löscher, W.: Einfluß klinisch gebräuchlicher Antikonvulsiva auf das γ-Aminobuttersäure-System bei der Maus. Inaug.-Diss., Freie Universität Berlin, Fachbereich Veterinärmedizin, 1975

  • Lowe, I. P., Robins, E., Eyermann, G. S.: The fluorimetric measurement of glutamic acid decarboxylase and its distribution in brain. J. Neurochem. 3, 8–18 (1958)

    Google Scholar 

  • Mao, C. C., Guidotti, A., Costa, E.: Evidence for an involvement of GABA in the mediation of the cerebellar cGMP decrease and the anticonvulsant action of diazepam. Naunyn-Schmiedeberg's Arch. Pharmacol. 289, 369–378 (1975)

    Google Scholar 

  • Meyer, H., Frey, H.-H.: Dependence of anticonvulsant drug action on central monoamines. Neuropharmacology 12, 939–947 (1973)

    Google Scholar 

  • Polc, P., Haefely, W.: Effects of two benzodiazepines, phenobarbitone and baclofen on synaptic transmission in the cat cuneate nucleus. Naunyn-Schmiedeberg's Arch. Pharmacol. 294, 121–131 (1976)

    Google Scholar 

  • Polzin, R., Barnes, C. D.: The effect of diazepam and picrotoxin on brainstem evoked dorsal root potentials. Neuropharmacology 15, 133–137 (1976)

    Google Scholar 

  • Roberts, E., Chase, T. N., Tower, D. B. (eds.): GABA in nervous system function. New York: Raven Press 1976

    Google Scholar 

  • Saad, S. F.: Effect of diazepam on γ-aminobutyric acid (GABA) content of mouse brain. J. Pharm. Pharmacol. 24, 839–840 (1972)

    Google Scholar 

  • Saad, S. F., Elmasry, A. F., Scott, P. M.: Influence of certain anticonvulsants on the concentrations of γ-aminobutyric acid in the central hemispheres of mice. Europ. J. Pharmacol. 17, 386–392 (1972)

    Google Scholar 

  • Salganicoff, L., De Robertis, E.: Subcellular distribution of the enzymes of the glutamic acid, glutamine and γ-aminobutyric acid cycles in rat brain. J. Neurochem. 12, 287–309 (1965)

    Google Scholar 

  • Salvador, R. A., Albers, R. W.: The distribution of glutamic-γ-aminobutyric transaminase in the nervous system of the rhesus monkey. J. biol. Chem. 234, 922–925 (1959)

    Google Scholar 

  • Sellström, A., Sjöberg, L.-B., Hamberger, A.: Neuronal and glial systems for γ-aminobutyric acid metabolism. J. Neurochem. 25, 393–398 (1975)

    Google Scholar 

  • Simler, S., Randrianarisoa, H., Lehmann, A., Mandel, P.: Effects du di-n-propylacétate sur les crises audiogènes de la souris. J. Physiol. (Paris) 60, 547 (1968)

    Google Scholar 

  • Simler, S., Ciesielski, L., Maitre, M., Randrianarisoa, H., Mandel, P.: Effect of sodium n-dipropylacetat on audiogenic seizures and brain γ-aminobutyric acid level. Biochem. Pharmacol. 22, 1701–1708 (1973)

    Google Scholar 

  • Straughan, D. W.: Convulsant drugs: amino acid antagonism and central inhibition. Neuropharmacology 13, 495–508 (1974)

    Google Scholar 

  • Straughan, D. W., Neal, M. J., Simmonds, M. A., Collins, G. G. S., Hill, R. G.: Evaluation of bicuculline as a GABA antagonist. Nature (Lond.) 233, 352–354 (1971)

    Google Scholar 

  • Steiner, F. A., Felix, D.: Antagonistic effects of GABA and benzodiazepines on vestibular and cerebellar neurones. Nature (Lond.) 260, 346–347 (1976)

    Google Scholar 

  • Sutton, J., Simmonds, M. A.: Effects of acute and chronic pentobarbitone on the γ-aminobutyric acid system in rat brain. Biochem. Pharmacol. 23, 1801–1808 (1974)

    Google Scholar 

  • Swinyard, E. A.: Laboratory assay of clinically effective antiepileptic drugs. J. Amer. pharm. Ass. 38, 201–204 (1949)

    Google Scholar 

  • Uchida, T., O'Brien, R. D.: The effects of hydrazines on rat brain 5-hydroxytryptamine, norepinephrine and gammaaminobutyric acid. Biochem. Pharmacol. 13, 725–730 (1964)

    Google Scholar 

  • Wood, J. D., Peesker, S. J.: The effect on GABA metabolism in brain of isonicotinic acid hydrazide (INH) and pyridoxine as a function of time after administration. J. Neurochem. 19, 1527–1537 (1972)

    Google Scholar 

  • Wood, J. D., Peesker, S. J.: The role of GABA metabolism in the convulsant and anticonvulsant actions of aminooxyacetic acid. J. Neurochem. 20, 379–387 (1973)

    Google Scholar 

  • Zakusov, V. V., Ostrovsdaya, R. U., Markovitch, V. V., Malodavkin, G. M., Bulayev, V. M.: Electrophysiological evidence for an inhibitory action of diazepam upon cat brain cortex. Arch. int. Pharmacodyn. 214, 188–205 (1975)

    Google Scholar 

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  1. Laboratorium für Pharmakologie und Toxikologie, Fachbereich Veterinärmedizin, Freie Universität Berlin, Koserstrasse 20, D-1000, Berlin 33

    W. Löscher & H. -H. Frey

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  1. W. Löscher
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  2. H. -H. Frey
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Löscher, W., Frey, H.H. Effect of convulsant and anticonvulsant agents on level and metabolism of γ-aminobutyric acid in mouse brain. Naunyn-Schmiedeberg's Arch. Pharmacol. 296, 263–269 (1977). https://doi.org/10.1007/BF00498692

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  • DOI: https://doi.org/10.1007/BF00498692

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