Differential effects of petit mal anticonvulsants and convulsants

1 Currents evoked by applications of y-aminobutyric acid (GABA) to acutely dissociated thalamic neurones were analysed by voltage-clamp techniques, and the effects of the anticonvulsant succinimides ethosuximide (ES) and a-methyl-a-phenylsuccinimide (MPS) and the convulsants tetramethylsuccinimide (TMS), picrotoxin, pentylenetetrazol (PTZ), and bicuculline methiodide were assessed. 2 TMS (1 juM-10mM) reduced responses to iontophoretically applied GABA, as did picrotoxin (0.1100uM), PTZ (1-100mM) and bicuculline (1-100pM). 3 ES, in high concentrations (1-10mM), 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 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.