Rat hippocampal somatostatin sst3 and sst4 receptors mediate anticonvulsive effects in vivo: Indications of functional interactions with sst2 receptors

Abstract

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, sst2 but not sst1 receptors play a critical role in the anticonvulsant effects of SRIF. At present, the role of rat sst3 and sst4 receptors in these anticonvulsive effects remains unknown. Here we demonstrate in vivo anticonvulsive actions of rat hippocampal sst3 and sst4 receptors. Using microdialysis and telemetry-based electroencephalographic recordings we show that intrahippocampal administration of the sst2 agonist L-779,976 (500 nM), the sst3 agonist L-796,778 (100 nM) or the sst4 agonist L-803,087 (100 nM) protects rats against focal pilocarpine-induced seizures. SRIF (1 μM)-, sst3- and sst4-mediated anticonvulsive actions are reversed by the selective sst2 receptor antagonist cyanamid 154806 (100 nM). Moreover, the selective sst3 antagonist SST3-ODN-8 (100 nM) blocks the sst4-mediated anticonvulsant effect. Sst3 antagonism does not reverse the sst2- or SRIF-mediated anticonvulsant effects. Our findings provide the first in vivo evidence for potent anticonvulsive properties of sst3 and sst4 receptors in the rat hippocampus. Nevertheless, selective sst2 receptor antagonism prevented these sst3- or sst4 receptor-mediated anticonvulsant effects, suggesting a functional cooperation with rat hippocampal sst2 receptors.