Abstract
We examined the effects of alkyl-substituted gamma-butyrolactones (GBLs), and gamma-thiobutyrolactones (TBLs) on GABA currents in cultured, voltage-clamped rat hippocampal neurons. Convulsant GBLs and TBLs reversiby diminished GABA responses in a concentration-dependent manner. beta-Ethyl-beta-methyl GBL (beta-EMGBL) completely abolished GABA responses at 3 mM (IC(50)390 microM), while TBL and beta-ethyl- beta-methyl TBL (beta-EMTBL)-induced inhibition of GABA currents was incomplete, saturating at about 50% of control at 300 microM and 10 mM for beta-EMTBL and TBL, respectively. beta-EMGBL and beta-EMTBL both increased the rate of decay of inhibitory post-synaptic currents (IPSCs) and beta-EMGBL also decreased IPSC peak amplitude. In contrast, the anticonvulsant alpha-ethyl-alpha-methyl TBL (alpha-EMTBL) potentiated GABA currents at all GABA concentrations tested; maximal potentiation was 190% of control at 1 mM alpha-EMTBL (EC50 102 microM). Another anticonvulsant alpha-ethyl-alpha-methyl GBL (alpha-EMGBL), potentiated responses to low (0.5 microM) but not high (greater than or equal to 10 microM) GABA. It also blocked the inhibitory effects of picrotoxin and beta-EMGBL and the facilitative effect of alpha-EMTBL on responses to 30 microM GABA. alpha-EMGBL did not interfere with other agents which augment GABA currents. Both alpha-EMTBL and alpha-EMGBL decreased the rate of IPSC decay without altering IPSC peak amplitude. None of these compounds had any direct membrane effects. We propose that beta-alkyl GBLs diminish GABA currents, and therefore, we hypothesize that these compounds are picrotoxin receptor agonists. beta- Alkyl TBLs partially diminish GABA currents and may be partial agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
