RT Journal Article
SR Electronic
T1 Repeated administration of SR 46349B, a selective 5-hydroxytryptamine2 antagonist, up-regulates 5-hydroxytryptamine2 receptors in mouse brain.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 84
OP 89
VO 43
IS 1
A1 M Rinaldi-Carmona
A1 C Congy
A1 J Simiand
A1 F Oury-Donat
A1 P Soubrie
A1 J C Breliere
A1 G Le Fur
YR 1993
UL http://molpharm.aspetjournals.org/content/43/1/84.abstract
AB 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.