Up-regulation of 5-HT2 receptors in the rat brain by repeated administration of SR 46349B, a selective 5-HT2 receptor antagonist.
Chronic administration (twice a day for three days and on the morning of the fourth day) of SR 46349B (trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3-(2-fluoroph enyl)propen-1- yl]phenol hemifumarate) (10 mg/kg, orally), a selective 5-HT2 receptor antagonist, caused 24 h later a marked increase (+42%) of the maximum binding capacity of [3H]ketanserin in rat brain cortical membranes without change in its affinity constant. Further, administration of the 5-HT2 receptor agonist, (+/-)-DOI((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) (1 mg/kg, i.p.), produced in chronic SR 46349B treated rats a significant increase in the amount of [3H]-inositol phosphate compared to corresponding controls. In addition, subacute administration of SR 46349B caused a 2-fold increase in the head-twitch response to (+/-)-DOI (0.5 mg/kg, i.p.). This enhanced response was blocked by an acute administration of ritanserin (6-(2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]ethyl]-7- methyl-5H-thiazolo[3,2-a]pyrimidin-5-one) (10 mg/kg). Finally, a significant enhancement (+29%) of 5-HT2 receptor mRNA levels was observed in the cortex. Taken together, these data showed that an up-regulation of 5-HT2 receptors occurred in rats following repeated treatment with a selective 5-HT2 receptor antagonist. The effects of SR 46349B on 5-HT2 receptors might implicate pre-translational regulation.
Rinaldi-Carmona
M
M
Sanofi Recherche, Montpellier France.
Bouaboula
M
M
Congy
C
C
Oury-Donat
F
F
Simiand
J
J
Shire
D
D
Casellas
P
P
Soubrié
P
P
Brelière
J C
JC
Le Fur
G
G
D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005464:Fluorobenzenes / Q000494:pharmacology*; D066298:In Vitro Techniques; D007291:Inosine Monophosphate / Q000378:metabolism; D007650:Ketanserin / Q000493:pharmacokinetics; D008297:Male; D008969:Molecular Sequence Data; D010636:Phenols / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000096:biosynthesis / Q000378:metabolism*; D016713:Ritanserin / Q000494:pharmacology; D015290:Second Messenger Systems / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
D000662:Amphetamines; D005464:Fluorobenzenes; D010636:Phenols; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C076033:SR 46349B; D007291:Inosine Monophosphate; D016713:Ritanserin; D007650:Ketanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine