Recent studies have demonstrated that ethanol potentiation of GABAA receptor function can be regulated by second-messenger-dependent processes. As a preliminary step to further characterize this interaction, we used the whole-cell patch-clamp technique to study the effects of guanosine phosphate analogs on ethanol potentiation of GABAA-mediated synaptic transmission in rat hippocampal CA1 neurons. Intracellular dialysis with 400 microM GDP beta S, an analog that inhibits G-protein coupled events, significantly reduced ethanol, but not pentobarbital, potentiation of IPSCs. In contrast, dialysing neurons with 100 microM GTP gamma S, an irreversible G-protein activator, selectively facilitated ethanol potentiation of GABAA IPSCs. These results suggest that one or more G-protein coupled events regulate the ethanol sensitivity of synaptic GABAA receptors.