UP-REGULATION OF 5-HT(2) RECEPTORS IN THE RAT-BRAIN BY REPEATED ADMINISTRATION OF SR-46349B, A SELECTIVE 5-HT(2) RECEPTOR ANTAGONIST

Chronic administration (twice a day for three days and on the morning of the fourth day) of SR 46349B thyl)oxyimino-3-(2-fluorophenyl)propen -1-yl]phenol hemifumarate) (10 mg/kg, orally), a selective 5-HT2 recep tor antagonist, caused 24 h later a marked increase ( + 42%) of the ma ximum binding capacity of [H-3]ketanserin in rat brain cortical membra nes without change in its affinity constant. Further, administration o f the 5-HT2 receptor agonist, /-)-1-(2,5-dimethoxy-4-iodophenyl)-2-ami nopropane) (I mg/kg, i.p.), produced in chronic SR 46349B treated rats a significant increase in the amount of [H-3]-inositol phosphate comp ared to corresponding controls. In addition, subacute administration o f 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 ac ute administration of ritanserin ethyl]-7-methyl-5H-thiazolo[3,2-a]pyr imidin-5-one) (10 mg/kg). Finally, a significant enhancement (+ 29%) o f 5-HT2 receptor mRNA levels was observed in the cortex. Taken togethe r, 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 implicat e pre-translational regulation.