The renin-angiotensin system is a powerful hormonal system, involving a number of bioactive peptides. Among these, angiotensin IV (Ang IV) gained a lot of interest since it is able to interfere with different brain functions such as learning and memory. In this study, we evaluated the anticonvulsant properties of Ang IV in the acute pilocarpine rat seizure model. Simultaneously, the neurochemical changes in the hippocampus were monitored using in vivo microdialysis coupled to microbore liquid chromatography. Intracerebroventricularly (i.c.v.) administered Ang IV protected rats against seizures and caused a significant increase in the hippocampal extracellular dopamine and serotonin levels. Ang IV is an inhibitor of insulin-regulated aminopeptidase (IRAP), which metabolises different neuropeptides such as somatostatin-14, vasopressin and oxytocin. Among these, somatostatin-14 is presumed to have anticonvulsant effects. Indeed, i.c.v. administered somatostatin-14 also protected rats against seizures and caused increases of the hippocampal dopamine and serotonin levels. Moreover, the anticonvulsant effect as well as the increases of dopamine and serotonin induced by Ang IV could be blocked by concomitant i.c.v. administration of the somatostatin receptor 2 antagonist cyanamid 154806. These results reveal a possible role for dopamine and serotonin in the anticonvulsant effect of Ang IV and somatostatin-14. Our study shows that the ability of Ang IV to inhibit pilocarpine-induced convulsions is dependent on somatostatin receptor 2 activation and is possibly mediated via inhibition of IRAP resulting in an elevated concentration of somatostatin-14 in the brain.