Summary
The intraperitoneal administration of gabaculine, aminooxyacetic acid (s.c.), γ-acetylenic GABA, γ-vinyl GABA, ethanolamine-O-sulphate, sodium valproate and GABA caused significant increases in the GABA content of both the whole brain and brain nerve endings (synaptosomes) in mice, a linear relationship being observed between the two parameters. When the relative effects on GABA concentrations were compared with the potency of the different drugs to elevate the thresholds for electroconvulsions and clonic pentetrazole seizures, only the increase in the pentetrazole seizure threshold was significantly correlated with the elevation of brain and synaptosomal GABA content. The present results indicate that the threshold for pentetrazole seizures is an appropriate test-system to study the relationship between alterations of overall GABA levels in the brain and nerve terminals and anticonvulsant activity of GABA-elevating agents.
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References
Abe M (1978) Relationship between γ-aminobutyric acid metabolism and antivitamin B6-induced convulsions. J Nutr Sci Vitaminol 24:419–427
Abe M, Matsuda M (1977) γ-Aminobutyric acid metabolism in subcellular particles of mouse brain and its relationship to convulsions. J Biochem 82:195–200
Balázs R, Machiyama Y, Hammond BJ, Julian T, Richter D (1970) The operation of the γ-aminobutyrate bypath of the tricarboxyclic acid cycle in brain tissue in vitro. Biochem J 116:445–467
Enna SJ, Snyder SH (1976) A simple, sensitive and specific radioreceptor assay for endogenous GABA in brain tissue. J Neurochem 26:221–224
Frey H-H (1976) Elevation of central γ-aminobutyric acid levels by isoniazid in mice and convulsant thresholds. Biochem Pharmacol 25:1216–1219
Frey H-H, Popp C, Löscher W (1979) Influence of inhibitors of the high affinity GABA uptake on seizure thresholds in mice. Neuropharmacology 18:581–590
Hint HC, Richter AW (1958) A simple intravenous infusion technique for mice. Acta Pharmacol (Kbh) 14:153–157
Kimball AW, Burnett WT, Doherty DG (1957) Sampling methods for screening compounds in radiation protection studies with mice. Radiat Res 7:1–12
Löscher W (1979a) 3-Mercaptopropionic acid: convulsant properties, effects on enzymes of the γ-aminobutyrate system in mouse brain and antagonism by certain anticonvulsant drugs, aminooxyacetic acid and gabaculine. Biochem Pharmacol 28:1397–1407
Löscher W (1979b) GABA in plasma and cerebrospinal fluid of different species. Effects of γ-acetylenic GABA, γ-vinyl GABA and sodium valproate. J Neurochem 32:1587–1591
Löscher W (1980) A comparative study of the pharmacology of inhibitors of GABA-metabolism. Naunyn-Schmiedeberg's Arch Pharmacol 315:119–128
Löscher W (1981a) Zum Wirkungsmechanismus der Antiepileptika. Tierexperimentelle Befunde zur Bedeutung von Neurotransmittern. Nervenarzt 52:61–67
Löscher W (1981b) Effect of inhibitors of GABA aminotransferase on the metabolism of GABA in brain tissue and synaptosomal fractions. J Neurochem 36:1521–1527
Löscher W (1981c) Valproate induced changes in GABA metabolism at the subcellular level. Biochem. Pharmacol 30:1364–1366
Löscher W, Frey H-H (1977) 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
Markwell MAK, Haas SM, Bieber LL, Tolbert NE (1978) A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal Biochem 87:206–210
Matsuda M, Abe M, Hoshino M, Sakurai T (1979) γ-Aminobutyric acid in subcellular fractions of mouse brain and its relation to convulsions. Biochem Pharmacol 28:2785–2789
Meldrum B (1979). Convulsant drugs, anticonvulsants and GABA-mediated neuronal inhibition. In: Krogsgaard-Larsen P, Scheel-Krüger J, Kofod H (eds) GABA-Neurotransmitters. Munksgaard, Copenhagen, pp 390–405
Schmidt D (1980) Neurotransmitter und Epilepsien. Klinische Gesichtspunkte zur Rolle der biogenen Amine, der γ-Aminobuttersäure und Taurin für die Anfallsregulation von Patienten mit Epilepsie. Nervenarzt 51:582–590
Wood JD (1975) The role of γ-aminobutyric acid in the mechanism of seizures. Prog Neurobiol 5:77–95
Wood JD, Kurylo E, Newstead JD (1978) Aminooxyacetic acid induced changes in γ-aminobutyrate metabolism at the subcellular level. Canad J Biochem 56:667–672
Wood JD, Russell MP, Kurylo E, Newstead JD (1979) Stability of synaptosomal GABA levels and their use in determining the in vivo effects of drugs: convulsant agents. J Neurochem 33:61–68
Wood JD, Russell MP, Kurylo E (1980a) The γ-aminobutyrate content of nerve endings (synaptosomes) in mice after intramuscular injection of γ-aminobutyrate-elevating agents: a possible role in anticonvulsant activity. J. Neurochem 35:125–130
Wood JD, Schousboe A, Krogsgaard-Larsen P (1980b) In vivo changes in the GABA content of nerve endings (synaptosomes) induced by inhibitors of GABA uptake. Neuropharmacology 19:1149–1152
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Löscher, W. Relationship between drug-induced changes in seizure thresholds and the GABA content of brain and brain nerve endings. Naunyn-Schmiedeberg's Arch. Pharmacol. 317, 131–134 (1981). https://doi.org/10.1007/BF00500068
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DOI: https://doi.org/10.1007/BF00500068