Flumazenil prevents diazepam-elicited anticonvulsant action and concomitant attenuation of glutamate overflow.
Systemic administration of diazepam (5 mg/kg, i.p.) produced a prompt anticonvulsant effect in pilocarpine-induced seizures in freely moving rats. The anticonvulsant effect was associated with significant attenuation of pilocarpine-evoked increases in extracellular hippocampal glutamate levels to below the baseline levels. The purpose of the present microdialysis study, therefore, was to investigate if the effect of diazepam on glutamate release was mediated at the level of the benzodiazepine gamma-aminobutyric acid(A) (GABA(A)) receptor complex to preclude any non-GABAergic mechanisms. Systemic administration of the specific benzodiazepine-receptor antagonist flumazenil (10 mg/kg, i.p. )-elicited complete reversal of diazepam-evoked anticonvulsant action and concomitant attenuation of extracellular glutamate efflux below the baseline levels. This provides evidence that under the given experimental conditions, diazepam-evoked alterations in glutamate overflow associated with the anticonvulsant action were indeed mediated at the level of benzodiazepine-GABA(A) receptor complex, possibly involving the modulation of both pre- and post-synaptic sites of the receptor complex.
Khan
G M
GM
Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
Smolders
I
I
Ebinger
G
G
Michotte
Y
Y
D000818:Animals; D000927:Anticonvulsants / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D003292:Convulsants; D003975:Diazepam / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D018698:Glutamic Acid / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D010862:Pilocarpine; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
D000927:Anticonvulsants; D003292:Convulsants; D018757:GABA Modulators; D011963:Receptors, GABA-A; D010862:Pilocarpine; D018698:Glutamic Acid; D005442:Flumazenil; D003975:Diazepam