Postsynaptic 5-HT 1B receptors modulate electroshock-induced generalised seizures in rats

Abstract

Although an important regulatory role for serotonin (5-HT) in seizure activation and propagation is well established, relatively little is known of the function of specific 5-HT receptor subtypes on seizure modulation. The aim of the present study was to investigate the role of 5-HT 1A, 1B and 1D receptors in modulating generalised seizures in the rat maximal electroshock seizure threshold (MEST) test. The mixed 5-HT receptor agonists SKF 99101 (5-20 mg kg -1 i.p.) and RU 24969 (1-5 mg kg -1 Lp.), 0.5 h pretest, both produced marked dose-related increases in seizure threshold. These agents share high affinity for 5-HT 1A, 1B and 1D receptors. Antiseizure effects induced by submaximal doses of these agonists were maintained following p-chlorophenylalanine (150 mg kg -1 i.p. × 3 days)-induced 5-HT depletion. The anticonvulsant action of both SKF 99101 (15 mg kg -1 i.p.) and RU 24969 (2.5 mg kg -1 i.p.) was dose-dependently abolished by the selective 5-HT 1B receptor antagonist SB-224289 (0.1-3 mg kg -1 p.o., 3 h pretest) but was unaffected by the selective 5-HT 1A receptor antagonist WAY 100635 (0.01-0.3 mg kg -1 s.c., 1 h pretest). This indicates that 5-HT 1B receptors are primarily involved in mediating the anticonvulsant properties of these agents. In addition, the ability of the 5-HT 1B/1D receptor antagonist GR 127935 (0.3-3 mg kg -1 s.c., 60 min pretest) to dose-dependently inhibit SKF 99101-induced elevation of seizure threshold also suggests possible downstream involvement of 5-HT 1D receptors in the action of this agonist, although confirmation awaits the identification of a selective 5-HT 1D receptor antagonist. Overall, these data demonstrate that stimulation of postsynaptic 5-HT 1B receptors inhibits electroshock-induced seizure spread in rats. © 2005 Nature Publishing Group. All rights reserved.