Anticonvulsant and proconvulsant effects of inhibitors of GABA degradation in the amygdala-kindling model.
The effects of three drugs, namely gamma-vinyl GABA (vigabatrin), gamma-acetylenic GABA, and aminooxyacetic acid, which increase brain GABA concentrations by irreversible inhibition of GABA degradation, were studied in amygdala-kindled rats. Vigabatrin 800 or 1,200 mg/kg i.p. 4 h after its administration, caused prolongation of behavioural seizures and electrographic afterdischarges recorded from the stimulated amygdala. One to three days after administration it dose dependently reduced seizure severity, seizure duration and afterdischarge duration in most animals. Determination of GABA levels in synaptosomes isolated from 12 brain regions of kindled rats 4 or 48 h after injection of 1,200 mg/kg vigabatrin indicated that the variable effects of this drug at different times after its administration could be related to differences in the time course of nerve terminal GABA increases in selective brain regions such as amygdala and corpus striatum. In contrast to vigabatrin, gamma-acetylenic GABA, 100 mg/kg i.p., reduced seizure severity in kindled rats as early as 4 h after its administration but afterdischarge duration increased significantly on subsequent days. Similar late increases in afterdischarge duration (and limbic seizure activity) after the time of maximum anticonvulsant effect had elapsed were also observed with vigabatrin, which could suggest that the anticonvulsant effect of such drugs is followed by withdrawal hyperexcitability. Aminooxyacetic acid, 20 mg/kg i.p., exerted no significant anticonvulsant effect in kindled rats but prolonged afterdischarge duration in several of the animals studied. The data suggest that GABA-T inhibitors, such as vigabatrin, differ from most antiepileptic drugs previously tested in the kindling model in that they may produce both anticonvulsant and proconvulsant effects at the same dose in the same animal as a function of time after administration.
Löscher
W
W
Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, F.R.G.
Jäckel
R
R
Müller
F
F
D000480:Alkynes; D000614:Aminocaproates / Q000494:pharmacology; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors; D007696:Kindling, Neurologic; D008297:Male; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000480:Alkynes; D000614:Aminocaproates; D000927:Anticonvulsants; D000625:Aminooxyacetic Acid; D005680:gamma-Aminobutyric Acid; C013785:4-amino-5-hexynoic acid; D005968:Glutamate Decarboxylase; D020888:Vigabatrin