title: 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, 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.
authors.affiliation: Center for Neuroscience, Department of Pharmaceutical Chemistry and Drug Analysis, CePhar, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium.
authors.forename: Najat
authors.initials: N
authors.lastname: Aourz
authors.forename: Dimitri
authors.initials: D
authors.lastname: De Bundel
authors.forename: Bart
authors.initials: B
authors.lastname: Stragier
authors.forename: Ralph
authors.initials: R
authors.lastname: Clinckers
authors.forename: Jeanelle
authors.initials: J
authors.lastname: Portelli
authors.forename: Yvette
authors.initials: Y
authors.lastname: Michotte
authors.forename: Ilse
authors.initials: I
authors.lastname: Smolders
mesh_terms: D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004569:Electroencephalography; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D017551:Microdialysis; D009578:Nitrobenzenes / Q000494:pharmacology / Q000627:therapeutic use; D010862:Pilocarpine / Q000009:adverse effects; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D013004:Somatostatin / Q000627:therapeutic use
chemical_list: D000577:Amides; D000927:Anticonvulsants; D007211:Indoles; C121854:L 779976; C429627:L796778; C429628:L803087; D009578:Nitrobenzenes; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; C106140:somatostatin receptor sst2A; C098681:somatostatin receptor subtype-4; D010862:Pilocarpine; D013004:Somatostatin