Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction.
1. Succinimide derivatives can be either convulsant (tetramethylsuccinimide (TMS)), or anticonvulsant (ethosuximide (ES); alpha-methyl-alpha-phenylsuccinimide (MPS)). ES, an anticonvulsant succinimide, has previously been shown to block calcium currents of thalamic neurones, while the convulsant succinimide TMS blocks gamma-aminobutyric acid (GABA) responses in a similar fashion to the convulsant pentylenetetrazol (PTZ). 2. Using voltage-clamp techniques, we analysed the effects of the anticonvulsant succinimides ES and MPS and the convulsants TMS and PTZ on calcium currents of acutely isolated thalamic relay neurones of the rat. 3. MPS and ES reduced low-threshold calcium current (LTCC) in a voltage-dependent manner, without affecting steady-state inactivation. MPS was less potent than ES (IC50 of 1100 vs 200 microM) but greater in efficacy (100% maximal reduction vs 40% for ES). 4. PTZ had no effect on calcium currents, and TMS only reduced LTCC at very high concentrations, and did not occlude MPS effects when applied concurrently. 5. These results, which demonstrate that anticonvulsant, but not convulsant, succinimides block LTCC, provide additional support for the hypothesis that LTCC reduction is a mechanism of action of the anticonvulsant succinimides related to their effects in petit mal epilepsy.
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*; D015220:Calcium Channels / Q000187:drug effects*; D003292:Convulsants / Q000494:pharmacology*; D004832:Epilepsy, Absence / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D005013:Ethosuximide / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000494:pharmacology; D013788:Thalamus / Q000166:cytology* / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000927:Anticonvulsants; D015220:Calcium Channels; D003292:Convulsants; D013388:Succinimides; C018504:N-desmethylmethsuximide; C040664:3,3,4,4-tetramethylsuccinimide; D005680:gamma-Aminobutyric Acid; D005013:Ethosuximide; D010433:Pentylenetetrazole