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

1 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. 2 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. 3 The mixed 5‐HT receptor agonists SKF 99101 (5–20 mg kg −1 i.p.) and RU 24969 (1–5 mg kg −1 i.p.), 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. 4 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. 5 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. 6 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. 7 Overall, these data demonstrate that stimulation of postsynaptic 5‐HT 1B receptors inhibits electroshock‐induced seizure spread in rats.British Journal of Pharmacology (2005) 144 , 628–635. doi: 10.1038/sj.bjp.0706027