Effects of anticonvulsant lactams on in vitro seizures in the hippocampal slice preparation

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 chlor ide currents, which is thought to be the mechanism by which they exert thei r therapeutic effects. However, the apparent affinity for these GABA(A) int eractions is low: EC(50)s range from hundreds of micromolar to low millimol ar 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 wh ich this occurs. To address these questions, we used two methods of inducin g ictal activity in hippocampal-entorhinal cortical slices: 54-aminopyridin e (4-AP) and low Mg2+. We found that 3,3-diethyl-2-pyrrolidinone (diethyl-l actam) prevents seizure-like discharges with IC(50)s of 1.1 and 2.1 mM in t he two models, respectively. These values are nearly identical to the EC50 value obtained in whole-cell studies of diethyl-lactam's GABA(A) receptor m odulation. 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-meth yl-gamma-thiobutyrolactone (alpha-EMTBL), two compounds which are similar t o diethyl-lactam, but demonstrate picrotoxin-insensitive inhibition of volt age-dependent currents, diminished low Mg2+/picrotoxin seizure activity. Ou r results support the hypothesis that diethyl-lactam and related compounds exert their anticonvulsant activity primarily, if not exclusively, by modul ating the GABA(A) receptor. (C) 1999 Published by Elsevier Science B.V. All rights reserved.