PT  - JOURNAL ARTICLE
AU  - E Lin-Michell
AU  - A Y Chweh
AU  - E A Swinyard
TI  - Effect of ethosuximide alone and in combination with gamma-aminobutyric acid receptor agonists on brain gamma-aminobutyric acid concentration, anticonvulsant activity and neurotoxicity in mice.
DP  - 1986 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 486--489
VI  - 237
IP  - 2
4099  - http://jpet.aspetjournals.org/content/237/2/486.short
4100  - http://jpet.aspetjournals.org/content/237/2/486.full
SO  - J Pharmacol Exp Ther1986 May 01; 237
AB  - The acute administration of an anticonvulsant dose of ethosuximide (150 mg/kg) had no effect on brain gamma-aminobutyric acid (GABA) concentration, whereas a toxic dose (400 mg/kg) increased significantly the concentration of brain GABA (1.23 +/- 0.05 vs. 1.92 +/- 0.14 mumol/g of wet tissue). The administration of 500 mg/kg/day of ethosuximide for 1, 2, 4, 6, 8 and 11 days induced neurotoxicity in 100, 100, 67, 0, 0 and 0% of animals, respectively, and increased brain GABA concentration 46, 38, 25, 14, 9 and 0%, respectively. These results imply that the tolerance that develops in response to the chronic administration of toxic doses of ethosuximide correlates well with the concentration of brain GABA. 4,5,6,7-Tetrahydroisoxazolo [5,4-c]pyridin-3-ol even in toxic doses had no effect on the anticonvulsant activity of ethosuximide. Combination studies with ethosuximide and progabide demonstrated that the antipentylenetetrazol activity of the individual components interacts additively. Likewise, combinations of either ethosuximide and 4,5,6-tetrahydroisoxazolo [5,4-c]pyridin-3-ol or ethosuximide and progabide showed an additive effect by the rotorod test. These results indicate that the antipentylenetetrazol activity of ethosuximide is unrelated to GABA function and that the increase in brain GABA concentration induced by toxic doses of ethosuximide contributes to its neurotoxicity.