Physiological Regulation of the Picrotoxin Receptor by r=Butyrolactones and y-Thiobutyrolactones in Cultured Hippocampal Neurons

We examined the effects of alkyl-substituted y-butyrolactones (GBLs), and y-thiobutyrolactones (TBLs) on GABA currents in cultured, voltage-clamped rat hippocampal neurons. Convulsant GBLs and TBLs reversibly diminished GABA responses in a concentration-dependent manner. @-Ethyl+methyl GBL (&EMGBL) completely abolished GABA responses at 3 rnh! (I&,, 390 PM), while TBL and @-ethyl-&methyl TBL (&EMTBL)-induced inhibition of GABA currents was incomplete, saturating at about 50% of control at 300 @I and 10 rnh! for &EMTBL and TBL, respectively. B-EMGBL and @-EMTBL both increased the rate of decay of inhibitory postsynaptic currents (IPSCs) and 8-EMGBL also decreased IPSC peak amplitude. In contrast, the anticonvulsant a-ethyl-amethyl TBL (a-EMTBL) potentiated GABA currents at all GABA concentrations tested; maximal potentiation was 190% of control at 1 mM a-EMTBL (EC,, 102 PM). Another anticonvulsant, a-ethyl-a-methyl GBL (a-EMGBL), potentiated responses to low (0.5 PM) but not high (2 10 PM) GABA. It also blocked the inhibitory effects of picrotoxin and @-EMGBL and the facilitative effect of a-EMTBL on responses to 30 PM GABA. a-EMGBL did not interfere with other agents which augment GABA currents. Both a-EMTBL and a-EMGBL decreased the rate of IPSC decay without altering IPSC peak amplitude. None of these compounds had any direct membrane effects. We propose that 8-alkyl GBLs diminish GABA currents, and therefore, we hypothesize that these compounds are picrotoxin receptor agonists. &Alkyl TBLs partially diminish GABA currents and may be partial agonists. a-Alkyl TBLs potentiate GABA currents and may be inverse agonists. Finally, a-EMGBL potentiates responses to low but not high GABA concentrations and may represent a mixed inverse agonist, antagonist at the picrotoxin receptor. The present results demonstrate that the picrotoxin receptor is capable of modulating GABA responses in opposing ways.