Effects of drugs acting on the GABA-benzodiazepine receptor complex on flurothyl-induced seizures in Mongolian gerbils.
In the present study, the mechanism behind flurothyl-induced seizures was examined using drugs acting on the GABA-benzodiazepine receptor complex in Mongolian gerbils. In addition, amino acid concentrations in the brain were also investigated. In behavioral experiments, the incidence of tonic extensor was 83.3% in both the control and picrotoxin (0.5 mg/kg)-treated groups, 0% in the valproate (200 mg/kg)-treated group, and 50% in the picrotoxin plus valproate-treated group. However, picrotoxin did not antagonize the effect of valproate on clonic seizure latency at all. Flumazenil, a benzodiazepine receptor antagonist, was found to have an inhibitory effect on the anticonvulsant action of diazepam (0.5 mg/kg). The incidence of tonic extensor was 83.3% in flumazenil (10 mg/kg)-treated group, 0% in the diazepam (0.5 mg/kg)-treated group, and 83% in the flumazenil plus diazepam-treated group as well as the control group. Flumazenil also completely reversed the effect of diazepam on clonic seizure latency. In biochemical experiments, the concentration of the inhibitory amino acid, GABA, was significantly increased in the hippocampus (P<0.05) and cerebellum (P<0.01) in diazepam-treated animals. The increase of GABA in the hippocampus and cerebellum was antagonized by the administration of flumazenil. These results suggested that the anticonvulsant action of diazepam may be linked to increase in hippocampus and cerebellum GABA concentrations. The findings suggest that the mechanism of flurothyl-induced seizures, in part, is related to the highly sensitive benzodiazepine site of the GABA-benzodiazepine receptor complex.
Department of Hospital Pharmacy, Okayama University Medical School, 2-5-1, Shikata-cho, Okayama 700-8558, Japan. kgurfc15@cc.okayama-u.ac.jp
Yasuhiko
Y
Hashimoto
Hiroaki
H
Araki
Katsuya
K
Suemaru
Yutaka
Y
Gomita
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D005481:Flurothyl; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D005849:Gerbillinae; D008297:Male; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D014635:Valproic Acid / Q000494:pharmacology
D000596:Amino Acids; D000927:Anticonvulsants; D003292:Convulsants; D003975:Diazepam; D000431:Ethanol; D005442:Flumazenil; D005481:Flurothyl; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D010852:Picrotoxin; D011963:Receptors, GABA-A; D014635:Valproic Acid