Anticonvulsant actions have already widely been proven for somatostatin-14. Cortistatin-14 (CST-14) was shown in one report to protect against kainate-induced seizures (Braun et al. Brain Res.1998;803(1–2):54–60). Although these neuropeptides are products of different genes, they are structurally related. This explains the interaction of CST-14 with the SST receptors (sst1-sst5). We here used in vivo microdialysis and telemetry-based electrocorticography (ECoG) in rats and administered CST-14 (0.1mM–1mM–10mM) in the presence and absence of highly selective antagonists for sst2 and sst3 receptor subtypes via intrahippocampal administration. Seizures were evoked by intrahippocampal pilocapine perfusion (10mM,40min) and seizure severity was assessed using a previously validated behavioural scoring system. Moreover, behavioural seizure severity assessment was verified with ECoG in at least 2 rats of each test group treated with CST-14. ECoG recordings of the rats treated with 0.1mM CST-14 showed clear epileptic discharges following pilocarpine perfusion. Indeed, the test group treated with 0.1mM CST-14 was not protected against pilocarpine-induced seizure severity. In none of the rats epileptic discharges were recorded during treatment with 1mM and 10mM CST-14. Hence, intrahippocampal administration of 1mM and 10mM CST-14 was anticonvulsant against pilocarpine-induced seizures. Furthermore, we showed that the CST-14 (1mM)-mediated anticonvulsant actions were reversed in the presence of a selective sst2 receptor antagonist Cyanamid154806 (0.1mM) or a selective sst3 receptor antagonist SST3-ODN-8 (0.1mM). Intrahippocampal perfusion of the selective sst2 or the selective sst3 receptor antagonists alone did not affect the pilocarpine-induced seizure severity per se. In conclusion, our results show that CST-14 is able to prevent seizures in a focal pilocarpine rat model and that selective sst2 or selective sst3 receptor antagonism is able to abolish these anticonvulsant actions.