Summary
The effect of the “in vivo” administration of sodium valproate on t-[35S]butylbicyclophosphorothionate (35S-TBPS) binding measured “ex vivo” in the rat cerebral cortex was investigated. Sodium valproate produced a decrease of 35S-TBPS binding. The maximal effect (−32%) was reached with the dose of 400 mg/kg i. p., 60 min after the administration of the drug. Saturation experiments revealed that the effect of sodium valproate was due to a decrease in the total number of binding sites with no changes in the affinity constant. A small dose of diazepam (0.5 mg/kg, i. p.), which per se does not modify 35S-TBPS binding, markedly potentiated the inhibitory effect of sodium valproate on 35S-TBPS binding. Moreover, the “in vitro” addition of sodium valproate to cortical membranes failed to modify 35S-TBPS binding, indicating that the effect of the “in vivo” administration of this drug is not due to its direct interaction with the chloride associated binding sites. These results strongly suggest that this drug enhances the function of GABAergic synapses at the level of the GABA-coupled chloride channel. This conclusion supports the hypothesis that an enhancement of GABAergic transmission plays a role in the molecular mechanism involved in the antiepileptic action of sodium valporate.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anlezark G, Horton RW, Meldrum BS, Sawaya MCB (1976) Anticonvulsant action of ethanolamine-o-sulphate and di-n-propylacetate and the metabolism of γ-aminobutyric acid (GABA) in mice with anxiogenic seizures. Biochem Pharmacol 25: 413–417
Biggio G (1983) The action of stress, β-carbolines, diazepam and Ro 15–1788 on GABA receptors in the rat brain. In: Biggio G, Costa E (eds) Benzodiazepine recognition site ligands: biochemistry and pharmacology. Raven Press, New York, pp 105–117
Buchhalter JR, Dichter MA (1986) Effect of valproic acid in cultured mammalian neurons. Neurology 36:259–262
Chapman A, Keane PE, Meldrum BS, Simiand J, Vernieres JC (1982) Mechanism of anticonvulsant action of valproate. Progr Neurobiol 19:315–359
Concas A, Serra M, Atsoggiu T, Biggio G (1988) Foot-shock stress and anxiogenic β-carbolines increase t-[35S]butylbicyclophos-phorothionate binding in the rat cerebral cortex, an effect opposite to anxiolytic and γ-aminobutyric acid mimetics. J Neurochem 51:1868–1876
Dulac O, Arthuis M (1984) Open trials with valproate in epilepsy. Epilepsia 25:S23-S31
Fariello R, Smith MC (1989) Valproate mechanisms of action. In: Levy R, Mattson R, Meldrum B, Penry JK, Dreifuss FE (eds) Antiepileptic drugs. Raven Press, New York, pp 567–575
Gee KW, Lawrence LJ, Yamamura HI (1986) Modulation of the chloride ionophore by benzodiazepine receptor ligands: influence of γ-aminobutyric acid and ligand efficacy. Mol Pharmacol 30:218–255
Gent JP, Phillips NI (1980) Sodium di-n-propylacetate (valproate) potentiates responses to GABA and muscimol on single central neurones. Brain Res 197:275–278
Godin Y, Heiner L, Mark J, Mandel P (1969) Effects of di-npropylacetate, an anticonvulsive compound, on GABA metabolism. J Neurochem 16:869–873
Gram L, Drachmann Bentsen K (1985) Valproate: an updated review. Acta Neurol Scand 72:129–139
Harrison NL, Simmonds MA (1982) Sodium valproate enhances responses to GABA receptor activation only at high concentrations. Brain Res 250:201–204
Kerwin RW, Olpe HR, Schmutz M (1980) The effect of sodium n-dipropyl acetate on γ-aminobutyric acid-dependent inhibition in the rat cortex and substantia nigra in relation to its anticonvulsant activity. Br J Pharmacol 71:545–551
Kerwin RW, Taberner PV (1981) The mechanism of action of sodium valproate. Gen Pharmacol 12:71–75
Kulkarni SK, Mehta AK, Ticku M (1990) Comparison of anticonvulsant effect of ethanol against NMDA-, kainic acid- and picrotoxin-induced convulsions in rats. Life Sci 46:481–487
Löscher W (1980) Effect of inhibitors of GABA transaminase on the synthesis binding uptake, and metabolism of GABA. J Neurochem 34:1603–1608
Löscher W (1981) Effect of inhibitor of GABA aminotransferase on the metabolism of GABA in brain tissue and synaptosomal fractions. J Neurochem 36:1521–1527
Löscher W (1985) Valproic acid. In: Frey HH, Janz D (eds) Antiepileptic Drugs, Handbook of experimental Pharmacology, Vol. 74, Springer, Berlin Heidelberg New York Tokyo, pp 507–536
Lowry OM, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
MacDonald RL, Bergey GK (1979) Valproic acid augments GABA-mediated postsynaptic inhibition in cultured mammalian neurons. Brain Res 170:558–562
Ramanjaneyulu RR, Ticku MK (1984) Binding characteristics and interactions of depressant drugs with [35S]t-butylbicyclophosphorothionate, a ligand that binds to the picrotoxin site. J Neurochem 42:221–229
Rastogi SK, Ticju MK (1985) Involvement of a GABAergic mechanism in the anticonvulsant effect of pentobarbital against maximal electroshock-induced seizures in rats. Pharmacol Biochem Behav 22:141–146
Sanna E, Concas A, Serra M, Biggio G (1989a) “In vivo” administration of anxiogenic β-carbolines enhances [35S]TBPS binding in the rat cerebral cortex. Eur J Neurosci Suppl 2:287
Sanna E, Serra M, Pepitoni S, Biggio G (1989b) Dramatic increase in nigral t-[35S]burylbicyclophosphorothionate binding sites elicited by the degeneration of the striato-nigral GABAergic pathway: reversal by diazepam. Brain Res 501:144–149
Sanna E, Concas A, Serra M, Biggio G (1990) In vivo administration of ethanol enhances the function of the GABA-dependent chloride channel in the rat cerebral cortex. J Neurochem 54:696–698
Sawaya MCB, Horton RW, Meldrum BS (1975) Effect of anticonvulsant drugs on the cerebral enzymes metabolizing GABA. Epilepsia 16:649–655
Serra M, Sanna E, Biggio G (1989) Isoniazid, an inhibitor of GABAergic transmission, enhances [35S]TBPS binding in rat cerebral cortex. Eur J Pharmacol 164:385–388
Skerritt JH, Johnston GAR (1983) Enhancement of GABA binding by benzodiazepines and related anxiolytics. Eur J Pharmacol 89:193–198
Squires RF, Casida JE, Richardson M, Saederup E (1983) 35S-t-butylbicyclophosphorothionate binds with high affinity to brain specific sites coupled to GABA-A and ion recognition site. Mol Pharmacol 23:326–336
Study RE, Barker JL (1981) Diazepam and (−)pentobarbital: fluctuation analysis reveals different mechanisms for potentiation of γ-aminobutyric acid responses in cultured central neurons. Proc Natl Acad Sci USA 78:7180–7184
Tassinari CA, Daniele O, Michelucci R, Bureau M, Dravet C, Roger J (1983) Benzodiazepines: efficacy in status epilepticus. In: Wasterlein CG, Treiman DM, Porter RJ (eds) Advances in neurology: status epilepticus. Raven Press, New York, pp 465–475
Ticku MK, Davis WC (1981) Effect of valproic acid on 3H-dihydropicrotoxinin binding sites at the benzodiazepines-GABA receptorionophores complex. Brain Res 223:218–222
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Concas, A., Mascia, M.P., Sauna, E. et al. “In vivo” administration of valproate decreases t-[35S]butylbicyclophosphorothionate binding in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 343, 296–300 (1991). https://doi.org/10.1007/BF00251129
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00251129