Abstract
Lamotrigine, carbamazepine and oxcarbazepine inhibit veratrine-induced neurotransmitter release from rat brain slices in concentrations corresponding to those reached in plasma or brain in experimental animals or humans after anticonvulsant doses, presumably due to their sodium channel blocking properties. Microdialysis measurements of extracellular glutamate and aspartate were carried out in conscious rats in order to investigate whether corresponding effects occur in vivo. Veratridine (10 μM) was applied via the perfusion medium to the cortex and the corpus striatum in the presence of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (1 mM in perfusion medium). Maximally effective anticonvulsant doses of carbamazepine (30 mg/kg), oxycarbazepine ( 60 mg/kg) and lamotrigine (15 mg/kg) were given orally.
The uptake inhibitor increased extracellular glutamate and aspartate about 2-fold in striatum and about 7-fold and 3-fold, respectively, in cortex. Veratridine caused a further 2–3-fold increase in extracellular glutamate in striatum and cortex, respectively, but its effect on extracellular aspartate was less marked in both areas. None of the anticonvulsant compounds affected the veratridine-induced increases in extracellular glutamate or aspartate in the striatum which were, however, markedly inhibited by tetrodotoxin (1 μM) and thus are sensitive to sodium channel blockade. In the cortex, the same drugs at the same doses did cause about 50% inhibition of the veratridine-induced increase in extracellular glutamate. Carbamazepine and to a lesser extent lamotrigine, but not oxcarbazepine, also inhibited the veratridine-induced increase in extracellular aspartate in the cortex.
Although our results might seem to support the view that inhibition of glutamate and aspartate release is responsible for the anticonvulsant effects of lamotrigine, carbamazepine and oxcarbazepine, two complementary findings argue against this interpretation. First, as previously shown, inhibition of electrically induced release of glutamate requires 5 to 7 times higher concentrations of these compounds than release elicited by veratrine. Second, the present study indicates that doses totally suppressing convulsions caused no inhibition in the striatum and at best a 50% inhibition in the brain cortex. From this we conclude that the doses used here, although to some extent effective against veratridine, did not suppress the release of GLU and ASP elicited by the normal ongoing electrical activity of the glutamatergic and aspartatergic neurons and that the mechanism of the suppression of convulsions must be sought elsewhere.
Similar content being viewed by others
References
Ahmad S, Fowler LJ, Leach MJ, Whitton PS (1995) Lamotrigine alters veratridine- but not K+-evoked amino acid release in the ventral hippocampus of the rat in vivo. Br J Pharmacol 115,116P
Andermann F (1994) Oxcarbazepine: experience and future role. Epilepsia 35 [Suppl 3]:S1-S31
Baltzer V, Schmutz M (1978) Experimental anticonvulsant properties of GP 47680 and of GP 47779, its main human metabolite; compounds related to carbamazepine. In: Meinardi H, Rowan AJ (eds) Advances in epileptology: 9th epilepsy int. symposium. Swets & Zeitlinger B.V., Amsterdam, pp 295–299
Budavari S, O'Neill MJ, Smith A, Heckelman PE (1989) Merck Index, 11th edn. Merck & Co., Rahway
Butcher SP, Hamberger A (1987) In vivo studies on the extracellular, and veratrine-releasable, pools of endogenous amino acids in the rat striatum: effects of corticostriatal deafferentition and kainic acid lesion. J Neurochem 48:713–721
Cheung H, Kamp D, Harris E (1992) An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Res 13:107–112
Crowder JM, Bradford HF (1987) Common anticonvulsants inhibit Ca2+ uptake and amino acid neurotransmitter release in vitro. Epilepsia 28:378–382
Dam M, Ekberg R, Loyning Y, Waltimo O, Jacobsen K (1989) A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 3:70–76
Finney DJ (1971) Probit analysis, 3rd edn. Cambridge University Press, Cambridge
Goa KL, Ross SR, Chrisp P (1993) Lamotrigine. A review of its pharmacological properties and clinical efficacy in epilepsy. Drugs 46:152–176
Gram L, Philbert A (1986) Oxcarbazepine. In: Meldrum BS, Porter RJ (eds) New anticonvulsant drugs. John Libbey & Co., London, pp 229–235
Heron A, Lasbennes F, Seylaz J (1993) Adenosine modulation of amino acid release in rat hippocampus during ischemia and veratridine depolarization. Brain Res 608:27–32
Klosterskov-Jensen P, Gram L, Schmutz M (1991) Oxcarbazepine. In: Pisani F, Perucca E, Avanzini G, Richens A (eds) New antiepileptic drugs. Elsevier, Amsterdam, pp 135–140
Leach MJ, Marden CM, Miller AA (1986) Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia 27:490–497
Leach MJ, Baxter MG, Critchley MAE (1991) Neurochemical and behavioral aspects of lamotrigine. Epilepsia 32 [Suppl 2]:S4-S8
Lees G, Leach MJ (1993) Studies on the mechanism of action of the novel anticonvulsant lamotrigine (lamictal) using primary neuroglial cultures from rat cortex. Brain Res 612:190–199
Löschmann P-A, Eblen F, Wallner U, Wachtel H, Klockgether T (1995) Lamotrigine has no antiparkinsonian activity in rat models of Parkinson's disease. Eur J Pharmacol 284:129–134
Lu YM, Zhang JT, Zhao FQ, Qin YF (1991) Effects of Ca2+ antagonists on glutamate release and Ca2+ influx in the hippocampus with in vivo intracerebral microdialysis. Br J Pharmacol 104:222–226
Macdonald RL (1988) Anticonvulsant drug actions on neurons in cell culture. J Neural Transm 72:173–183
Macdonald RE, Kelly KM (1994) Mechanisms of action of currently prescribed and newly developed antiepileptic drugs. Epilepsia 35 [Suppl 4]:S41-S50
Martin P, Bernasconi R, Schiesser A, Bechtold M, Bernasconi P (1989) A new automated on line precolumn derivatisation system based on the WISP autosampler for the separation of amino acids by high performance liquid chromatography (HPLC). 13th Symp Column Liquid Chrom (Stockholm June 25–30, 1989) W-P029- (p 43) (abstr)
Masuda Y, Utsui Y, Shiraishi Y, Karasawa T, Yoshida K, Shimizu M (1979) Relationships between plasma concentrations of diphenylhydantoin, phenobarbital, carbamazepine and 3-sulfamoyl-methyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant or neurotoxic effects in experimental animals. Epilepsia 20:623–633
Mattson RH, Cramer JA, Collins JF, Smith DB, Delgado-Escueta AV, Browne TR, Williamson PD, Treiman DM, McNamara JO, McCutchen CB, Homan RW, Crill WE, Lubozynski MF, Rosenthal NP, Mayersdorf A (1985) Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 313: 145–151
McLean MJ, Schmutz M, Wamil AW, Olpe HR, Portet C, Feldmann KF (1994) Oxcarbazepine: mechanism of action. Epilepsia 35 [Suppl 3]:S5-S9
McMahon HT, Nicholls DG (1991) The bioenergetics of neurotransmitter release. Biochim Biophys Acta 1059:243–264
Mendez-Alvarez E, Soto-Otero R, Galan-Valiente J, Sierra-Marcuño G (1990) Effect of phenobarbital on carbamazepine and its major metabolites in serum, different brain areas, and urine after acute and chronic administration to rats. Epilepsia 31:202–210
Miller AA, Wheatley P, Sawyer DA, Baxter MG, Roth B (1986) Pharmacological studies on lamotrigine, a novel potential antiepileptic drug. I. Anticonvulsant profile in mice and rats. Epilepsia 27:483–489
Patsalos PN, Alavijeh MS, Brownhill W, Lascelles PT (1988) Effects of denzimol on carbamazepine and carbamazepine-10,11-epoxide concentrations in serum, liver, spleen and different brain regions of the rat: an inhibitory metabolic interaction. Naunyn-Schmiedeberg's Arch Pharmacol 337:111–114
Pellegrino LJ, Pellegrino AS, Cushman AJ (1979) A stereotaxic atlas of the rat brain, 2nd edn. Plenum Press, New York
Pellock JM (1994) Standard approach to antiepileptic drug treatment in the United States. Epilepsia 35 [Suppl 4]:S11-S18
Rambeck B, Schnabel R, May T, Jürgens U, Villagran R (1990) Postmortem serum protein binding and brain Concentrations of antiepileptic drugs in autoptic specimens from 45 epileptic patients. Ther Drug Monit 12:533–540
Rea MA, Ferriera S, Randolph W, Glass JD (1993) Daily profile of the extracellular concentration of glutamate in the suprachiasmatic region of the siberian hamster. Proc Soc Exp Biol Med 204:104–109
Renno WM, Mullett MA, Beitz AJ (1992) Systemic morphine reduces GABA release in the lateral but not the medial portion of the midbrain periaqueductal gray of the rat. Brain Res 594:221–232
Rogawski ME, Porter RJ (1990) Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 42:223–286
Schmutz M, Brugger F, Gentsch C, McLean MJ, Olpe HR (1994) Preclinical anticonvulsant profile and putative mechanisms of action. Epilepsia 35 [Suppl 5]:S47-S50
Schwarz JR, Grigat G (1989) Phenytoin and carbamazepine: potential-and frequency-dependent block of Na currents in mammalian myelinated nerve fibers. Epilepsia 30:286–294
Waldmeier PC, Baumann PA, Wicki P, Feldtrauer J-J, Stierlin C, Schmutz M (1995) Similar potency of carbamazepine, oxcarbazepine and lamotrigine in inhibiting the release of glutamate and other neurotransmitters. Neurology 45:1907–1913
Wamil AW, Portet Ch, Jensen PK, Schmutz M, McLean MJ (1991) Oxcarbazepine and its monohydroxy metabolite limit action potential firing by mouse central neurons in cell culture. Epilepsia 32 [Suppl 3]:65–66
Wamil AW, Schmutz M, Portet C, Feldmann KF, McLean MJ (1994) Oxcarbazepine and its monohydroxy metabolite limit action potential of neurons in vitro and protect rodents against generalized tonic-clonic seizures. Eur J Pharmacol 271:301–308
Willow M, Kuenzel EA, Catterall WA (1983) Inhibition of voltage sensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol Pharmacol 25:228–234
Young AMJ, Bradford HF (1986) Excitatory amino acid transmitters in the corticostriatal pathway: studies using intracerebral microdialysis in vivo. J Neurochem 47:1399–1404
Yuen AWC (1991) Lamotrigine. In: Pisani F, Perucca E, Avanzini G, Richens A (eds) New antiepileptic drugs. Elsevier, Amsterdam, pp 115–123
Yuen AWC (1994) Lamotrigine: a review of antiepileptic efficacy. Epilepsia 35 [Suppl 5]:S33-S36
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Waldmeier, P.C., Martin, P., Stöcklin, K. et al. Effect of carbamazepine, oxcarbazepine and lamotrigine on the increase in extracellular glutamate elicited by veratridine in rat cortex and striatum. Naunyn-Schmiedeberg's Arch Pharmacol 354, 164–172 (1996). https://doi.org/10.1007/BF00178716
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00178716