An analysis of anticonvulsant actions of GABA agonists (progabide and baclofen) in the kindling model of epilepsy.
The anticonvulsant action of progabide, an agonist of gamma-aminobutyric acid (GABA)A and GABAB receptors, was investigated in the kindling model of epilepsy in rats. Progabide shortened afterdischarge durations and attenuated the severity of the accompanying convulsive responses in previously kindled rats from the amygdala (AM), frontal cortex (FC), ventral and dorsal hippocampus (HIPP), in a dose-dependent manner. Although progabide was less effective in the dorsal HIPP kindled seizures, the efficacy was potent in AM, FC and ventral HIPP kindled seizures. On the other hand, the anticonvulsant action of baclofen, a selective agonist of GABAB receptors, was relatively weak in terms of the measurement of the afterdischarge duration of AM and HIPP kindled seizures even at toxic doses, compared with progabide. In addition, the anticonvulsant effects of progabide were partially reversed by treatment with the antagonist of benzodiazepine receptors, Ro 15-1788, whereas Ro 15-1788 administration alone did not alter AM kindled seizures. We concluded that the action of progabide may be mediated via the GABA/benzodiazepine receptor complex. These results support the hypothesis that a failure of GABAA-mediated inhibition is one of the bases of induction and generalization of seizures.
Sato
K
K
Department of Neuropsychiatry, Okayama University Medical School, Japan.
Morimoto
K
K
Okamoto
M
M
Nakamura
Y
Y
Otsuki
S
S
Sato
M
M
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D000927:Anticonvulsants; D011963:Receptors, GABA-A; C017985:progabide; D005680:gamma-Aminobutyric Acid; D001418:Baclofen