An initial observation that paired-pulse inhibition in hippocampal slices was increased rather than decreased by bicuculline prompted the present study to explore the mechanism underlying bicuculline-resistant inhibition. 2. In the presence of bicuculline, paired-pulse interactions were dependent on the interpulse interval (i.p.i.) but a medium-latency inhibition was consistently observed at an i.p.i. of 300 to 500 ms. 3. The medium-latency (300 ms) bicuculline-resistant inhibition produced by paired orthodromic stimuli was substantially reduced by 2-hydroxysaclofen and was probably largely mediated by GABAB-receptor activation. Paired-pulse inhibition produced by an orthodromic/antidromic stimulation sequence was not affected by 2-hydroxysaclofen suggesting the possibility that the GABAB-receptors involved in orthodromic inhibition may be located presynaptically on the Schaffer collateral terminals rather than on the postsynaptic surface. The medium latency inhibition was also reduced by baclofen and under some conditions, by adenosine. 4. In addition to the GABAB-component, a hydroxysaclofen-resistant depression of postsynaptic excitability contributed to bicuculline-resistant paired-pulse inhibition at the 300 ms latency.
