The effect of high helium pressure on inhibitory synaptic transmission was studied in rat hippocampal slices with extracellular recordings. Both feed-forward and recurrent GABAergic inhibition were tested in the CA1 region with paired-pulse stimulation paradigms. The efficiency of both types of inhibition decreased under high pressure (80 atm). However, the depression of synaptic and antidromic field potentials induced by perfusion of GABA or muscimol were not significantly affected by pressure. High pressure induced hyperexcitability of CA1 pyramidal cells. This effect was reduced by the application of 2-aminophosphonovalerate or GABA. The present results suggest that: (1) high pressure reduces the efficiency of the GABAergic inhibitory transmission but does not affect the sensitivity of GABAA receptors; (2) two different processes (reduction of GABAergic inhibition and facilitation of N-methyl-D-aspartate-mediated excitation) might be a direct consequence of the change in the voltage-sensitive ion channels under high pressure and might be involved in the development of the pressure-induced hyperexcitability of CA1 pyramidal cells.