Studies on the role of 5-HT2C and 5-HT2B receptors in regulating generalised seizure threshold in rodents.
The present studies were conducted to investigate the role of 5-HT2C and 5-HT2B receptors in the generation of pentylenetetrazol and electroshock-evoked seizures. The 5-HT2C/2B receptor-preferring agonist 1-(m-chlorophenyl)-piperazine (mCPP; 2.5-7 mg/kg i.p.) weakly elevated seizure threshold in the mouse (but not the rat) electroshock test and also provided appreciable protection against pentylenetetrazol-induced myoclonic and/or tonic seizures in mice and rats, an action that was inhibited by the 5-HT2C/2B receptor antagonist 5-methyl-1-(3-pyridylcarbomoyl)-1,2,3,5-tetrahydropyrrolo[2, 3-f]indole (SB-206553; 10-20 mg/kg p.o.). In contrast, the 5-HT2B receptor agonist 1-[5-(2-thienylmethoxy)-1H-3-indoyl]propan-2-amine hydrochloride (BW-723C86; 3-30 mg/kg s.c.) had no effect on the threshold for generalised seizures in any of the models employed. These results indicate that the observed anticonvulsant effects of mCPP are likely to be mediated by activation of 5-HT2C receptors. However, blockade of these receptors in mice (or rats) by SB-206553 (5-20 mg/kg p.o.) did not result in the reduced seizure threshold characteristic of mutant mice deficient of 5-HT2C receptors, suggesting that in normal adult animals this receptor subtype may usually be subjected to only a low level of 5-hydroxytryptamine tone.
Upton
N
N
Neurosciences Department, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK.
Stean
T
T
Middlemiss
D
D
Blackburn
T
T
Kennett
G
G
D000818:Animals; D004347:Drug Interactions; D004558:Electric Stimulation; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000209:etiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
C092430:1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine; D007211:Indoles; D011725:Pyridines; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013876:Thiophenes; C094868:SB 206553; D010433:Pentylenetetrazole