Some 3,3-disubstituted 2-pyrrolidinones and 2-piperidinones (five- and six-membered ring
lactams, respectively) possess potent in vivo
anticonvulsant activity. In vitro these
lactams potentiate
GABA(A) receptor-mediated
chloride currents, which is thought to be the mechanism by which they exert their
therapeutic effects. However, the apparent affinity for these
GABA(A) interactions is low: EC50s range from hundreds of micromolar to low millimolar values. In order to more completely characterize the activities of these compounds, it was necessary to know the concentrations required to curtail epileptiform activity in an intact neural network, and the mechanism by which this occurs. To address these questions, we used two methods of inducing ictal activity in hippocampal-entorhinal cortical slices:
4-aminopyridine (4-AP) and low Mg2+. We found that
3,3-diethyl-2-pyrrolidinone (
diethyl-lactam) prevents seizure-like discharges with IC50s of 1.1 and 2.1 mM in the two models, respectively. These values are nearly identical to the EC50 value obtained in whole-cell studies of
diethyl-lactam's
GABA(A) receptor modulation. The addition of the
GABA(A) antagonist
picrotoxin to the low Mg2+ ACSF produced
seizures which persisted during
diethyl-lactam application. Neither
3-benzyl-3-ethyl-2-piperidinone (3-BEP) nor alpha-ethyl-alpha-methyl-
gamma-thiobutyrolactone (
alpha-EMTBL), two compounds which are similar to
diethyl-lactam, but demonstrate
picrotoxin-insensitive inhibition of voltage-dependent currents, diminished low Mg2+/
picrotoxin seizure activity. Our results support the hypothesis that diethyllactam and related compounds exert their
anticonvulsant activity primarily, if not exclusively, by modulating the
GABA(A) receptor.