Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: GABA current blockade.
1. Currents evoked by applications of gamma-aminobutyric acid (GABA) to acutely dissociated thalamic neurones were analysed by voltage-clamp techniques, and the effects of the anticonvulsant succinimides ethosuximide (ES) and alpha-methyl-alpha-phenylsuccinimide (MPS) and the convulsants tetramethylsuccinimide (TMS), picrotoxin, pentylenetetrazol (PTZ), and bicuculline methiodide were assessed. 2. TMS (1 microM-10 microM) reduced responses to iontophoretically applied GABA, as did picrotoxin (0.1-100 microM), PTZ (1-100 mM) and bicuculline (1-100 microM). 3. ES, in high concentrations (1-10 mM), reduced GABA responses to a lesser extent, and also occluded the reductions in GABA-evoked currents produced by TMS, picrotoxin, and PTZ. ES did not occlude the effects of bicuculline on GABA responses. Therefore, we propose that ES acts as a partial agonist at the picrotoxin GABA-blocking receptor. 4. MPS had no effect on GABA responses (at a concentration of 1 mM), and, like ES, occluded the GABA-blocking actions of TMS, apparently acting as a full antagonist. 5. The anticonvulsant actions of ES and MPS against TMS and PTZ-induced seizures may thus involve two independent mechanisms: (1) the occlusion of TMS and PTZ GABA-blocking effects; and (2) the previously described specific effect of ES and MPS on low-threshold calcium current of thalamic neurones. The latter cellular mechanism may be more closely related to petit mal anticonvulsant activity.
Coulter
D A
DA
Department of Neurology and Neurological Sciences, Stanford University Medical Center, CA 94305.
Huguenard
J R
JR
Prince
D A
DA
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology*; D004832:Epilepsy, Absence / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D005013:Ethosuximide / Q000494:pharmacology; D066298:In Vitro Techniques; D007478:Iontophoresis; D009474:Neurons / Q000187:drug effects*; D010433:Pentylenetetrazole / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D013388:Succinimides / Q000494:pharmacology; D013788:Thalamus / Q000166:cytology* / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000927:Anticonvulsants; D001640:Bicuculline; D003292:Convulsants; D005013:Ethosuximide; D010433:Pentylenetetrazole; D010852:Picrotoxin; D013388:Succinimides; D005680:gamma-Aminobutyric Acid; C018504:N-desmethylmethsuximide; C040664:3,3,4,4-tetramethylsuccinimide