We investigated whether somatostain modulates the generation of long-term potentiation (LTP) in rat perforant path-dentate gyrus synapse in vivo. When somatostatin was injected intracerebroventricularly (i.c.v.) 20 min prior to the tetanus, the intensity of LTP increased dose dependently. Synaptic potential evoked by a low-frequency test stimulation, however, was not altered by somatostatin. We next tested whether the LTP-augmenting effect of somatostain is mediated by cholinergic activation, because somatostatin was demonstrated to promote acetylcholine release in rat hippocampal slice. Pirenzepine (50 nmol/rat), a muscarinic M1 receptor antagonist, did not affect the tetanus-induced LTP by itself. But when it was co-applicated with the somatostatin (50 ng/rat) 20 min before tetanus, it completely abolished the LTP-augmenting effect of somatostatin. Then we examined the effect of octreotide, a potent agonist specifically binding to somatostatin receptor subtypes 2 and 4, on the generation of LTP. Octreotide (500 ng/rat) also facilitated the intensity of LTP. These results suggest that somatostatin facilitates the generation of perforant path-dentate gyrus granule cell LTP by activating the muscarinic cholinergic receptor and the effect of somatostatin is induced, at least partly, by somatostatin receptor subtypes 2 and 4 in vivo.