The effects of the adenosine receptor antagonist 1,3-dimethyl-8-cyclopentylxanthine (cyclopentyltheophylline) and the enzyme adenosine deaminase have been examined on paired-pulse inhibition between orthodromic evoked field potentials in the CA1 region of the normal and disinhibited hippocampal slice. In the presence of the GABA A receptor antagonist (-)-bicuculline methobromide, cyclopentyltheophylline suppressed homosynaptic paired-pulse inhibition between stimuli 300 ms apart. Slices treated with (-)-bicuculline and cyclopentyltheophylline together tended to develop spontaneous burst potentials. In slices in which a surgical cut isolated the CA1 and CA3 areas, thereby preventing the development of bursts in CA1, the effect on paired-pulse inhibition was lessened but was still apparent. Adenosine deaminase, in the presence of (-)-bicuculline showed the same effect as cyclopentyltheophylline, decreasing substantially the amount of paired-pulse inhibition. These results suggest that adenosine may contribute to homosynaptic paired-pulse inhibition in disinhibited slices. For comparison, we also examined the effect of cyclopentyltheophylline in normal ((-)-bicuculline-free) slices. At 100 nM, cyclopentyltheophylline increased reversibly the size of orthodromically evoked synaptic population potentials in the CA1 region of the slices and also reduced reversibly the degree of homosynaptic paired-pulse inhibition between two stimuli delivered only 30 ms apart. This suggests that adenosine may also contribute to shorter latency paired-pulse inhibition in the normal hippocampal slice.