Postsynaptic 5-HT1B 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. x 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-HT1B receptor antagonist SB-224289 (0.1-3 mg kg(-1) p.o., 3 h pretest) but was unaffected by the selective 5-HT1A receptor antagonist WAY 100635 (0.01-0.3 mg kg(-1) s.c., 1 h pretest). This indicates that 5-HT1B 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-HT1D receptors in the action of this agonist, although confirmation awaits the identification of a selective 5-HT1D receptor antagonist. 7. Overall, these data demonstrate that stimulation of postsynaptic 5-HT1B receptors inhibits electroshock-induced seizure spread in rats.
Stean
Tania O
TO
Neurology & GI-CEDD, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW. Tania.Stean-1@gsk.com
Atkins
Alan R
AR
Heidbreder
Christian A
CA
Quinn
Leann P
LP
Trail
Brenda K
BK
Upton
Neil
N
D000818:Animals; D004597:Electroshock; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010881:Piperidones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects*; D044346:Receptor, Serotonin, 5-HT1D / Q000187:drug effects; D012640:Seizures / Q000188:drug therapy*; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology
D007211:Indoles; D010881:Piperidones; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; C108518:SB 22489G; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; D044282:Receptor, Serotonin, 5-HT1A; C108517:SKF 99101H; C025145:5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole