Somatostatin-14 (SRIF) is a potent anticonvulsant in rodent models of limbic seizures in which the hippocampus is its major site of action. However, the distribution of hippocampal sst receptors and their role in the anticonvulsant effects of SRIF remain controversial. Moreover, striking differences have been described between mice and rats. In rats, sst(2) but not sst(1) receptors play a critical role in the anticonvulsant effects of SRIF. At present, the role of rat sst(3) and sst(4) receptors in these anticonvulsive effects remains unknown. Here we demonstrate in vivo anticonvulsive actions of rat hippocampal sst(3) and sst(4) receptors. Using microdialysis and telemetry-based electroencephalographic recordings we show that intrahippocampal administration of the sst(2) agonist L-779,976 (500 nM), the sst(3) agonist L-796,778 (100 nM) or the sst(4) agonist L-803,087 (100 nM) protects rats against focal pilocarpine-induced seizures. SRIF (1 μM)-, sst(3)- and sst(4)-mediated anticonvulsive actions are reversed by the selective sst(2) receptor antagonist cyanamid 154806 (100 nM). Moreover, the selective sst(3) antagonist SST3-ODN-8 (100 nM) blocks the sst(4)-mediated anticonvulsant effect. Sst(3) antagonism does not reverse the sst(2)- or SRIF-mediated anticonvulsant effects. Our findings provide the first in vivo evidence for potent anticonvulsive properties of sst(3) and sst(4) receptors in the rat hippocampus. Nevertheless, selective sst(2) receptor antagonism prevented these sst(3)- or sst(4) receptor-mediated anticonvulsant effects, suggesting a functional cooperation with rat hippocampal sst(2) receptors.