This study was designed to examine the neuronal mechanisms of ethanol sensitivity by utilizing inbred short sleep (ISS) and inbred long sleep (ILS) mouse strains that display large differences in sensitivity to the behavioral effects of ethanol. Comparisons of whole- cell electrophysiological recordings from CA1 pyramidal neurons in hippocampal slices of ISS and ILS mice indicate that ethanol enhances GABA_A receptor- mediated inhibitory postsynaptic currents (GABA_A IPSCs) and reduces NMDA receptor- mediated excitatory postsynaptic currents (NMDA EPSCs) in a concentration and strain-dependent manner. In ILS neurons these receptor systems are significantly more ethanol sensitive than those in ISS neurons. To further examine the underlying mechanisms of differential ethanol sensitivities in these mice, GABA_B activity as well as presynaptic and postsynaptic ethanol actions were investigated. Inhibition of GABA_B receptor function enhances ethanol potentiation of distal GABA_A IPSCs in ILS but not ISS mice, and this blockade of GABA_B has no effect on ethanol's action on NMDA EPSCs in either mouse strain. Thus, subregional differences in GABA_B activity may contribute to the differential ethanol sensitivity of ISS and ILS mice. Moreover, analysis of ethanol effects on paired-pulse stimulation, spontaneous IPSC events, and brief local GABA or glutamate application suggest that postsynaptic rather than presynaptic mechanisms underlie the differential ethanol sensitivity of these mice. Furthermore, these results provide essential information to better focus on appropriate target sites for more effective drug development in the treatment of alcohol abuse.