The effect of exogenously applied somatostatin (1-14), which is one of the candidates of neuromodulators in the hippocampus, on long-term potentiation (LTP) was investigated in the CA1 and CA3 subfields of guinea-pig hippocampal slices. In the mossy fiber-CA3 pyramidal cell system, the magnitude of LTP of both population excitatory postsynaptic potential (pEPSP) and population spike was significantly augmented by somatostatin (10(-7)-10(-6)M) perfused before and during tetanic stimulation, which never affected basal amplitude of population spikes before tetanus. The enhancement of LTP by somatostatin lasted for at least one hour after washout. On the other hand, somatostatin at the most effective concentration (3.2 x 10(-7) M) in the above described system failed to affect the magnitude of the LTP of population spikes in Schaffer collateral-CA1 pathway. The enhancing effect of somatostatin on LTP in the mossy fiber CA3 system was inhibited either by a muscarinic antagonist, scopolamine (10(-6)M), or a beta-adrenoceptor antagonist, timolol (10(-6)M). These results suggest that somatostatin enhances the production of LTP in the mossy fiber-CA3 pathway of the guinea-pig hippocampus through the intervention of cholinergic and noradrenergic neurons.