Repeated administration of SR 46349B, a selective 5-hydroxytryptamine2 antagonist, up-regulates 5-hydroxytryptamine2 receptors in mouse brain.
Adaptive changes in 5-hydroxytryptamine (5-HT)2 receptors were investigated in mice after repeated administration of SR 46349B, a potent, selective, and competitive 5-HT2 receptor antagonist (Kl = 0.72 +/- 0.05 nM). Repeated administration (twice per day for 3 days and once on the morning of the fourth day) of SR 46349B (5 or 10 mg/kg, orally) caused 24 hr later a marked increase in 5-HT2 receptor number (+41% and +75%, respectively), measured ex vivo in brain cortical membranes with [3H] ketanserin, without affecting its affinity constant. Further, administration of the 5-HT2 agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane produced, in SR 46349B (10 mg/kg, orally)-treated mice, a significant stimulation of the 5-HT2 receptor-linked phosphoinositide turnover in vivo in the brain. In addition, subacute administration of SR 46349B (5 or 10 mg/kg, orally) caused a significant increase of the head-twitch response to L-5-hydroxytryptophan. This enhanced response was blocked by an acute administration of ritanserin (1 mg/kg). These results show that repeated administration of SR 46349B produced a parallel enhancement in 5-HT2 receptor number, in 5-HT2 receptor-linked signal transduction, and in 5-HT2 receptor-mediated behavioral responses in mice. These findings suggest for the first time that an up-regulation of 5-HT2 receptors can occur after repeated treatment with a selective 5-HT2 antagonist.
Rinaldi-Carmona
M
M
Sanofi Recherche, Montpellier, France.
Congy
C
C
Simiand
J
J
Oury-Donat
F
F
Soubrie
P
P
Breliere
J C
JC
Le Fur
G
G
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D005464:Fluorobenzenes / Q000494:pharmacology*; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D051379:Mice; D010636:Phenols / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000032:analysis / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D015854:Up-Regulation
D000662:Amphetamines; D005464:Fluorobenzenes; D007295:Inositol Phosphates; D010636:Phenols; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C076033:SR 46349B; D007650:Ketanserin; D006916:5-Hydroxytryptophan; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine