Regulation of 5-HT2A receptor mRNA levels and binding sites in rat frontalcortex by the agonist DOI and the antagonist mianserin

In the present study we have characterized the time course of effect of adm inistration of the serotonin(2) (5-HT2) receptor antagonist mianserin, or t he 5-HT2 receptor agonist (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminophenyl-2- aminopropane (DOI), on 5-HT2A receptor binding sites and mRNA levels in rat frontal cortex. Radioligand binding and ribonuclease protection assays wer e performed with separate hemispheres of frontal cortex from each animal to examine concomitant changes in 5-HT2A receptor sites and mRNA levels. The decrease in cortical 5-HT2A receptor sites in response to chronic DOI admin istration was not accompanied by changes in 5-HT2A receptor mRNA. A single injection of DOI produced a transient decrease in 5-HT2A receptor mRNA leve ls detected 1 h postinjection. The density of 5-MT, receptor sites, however , was not significantly reduced following a single injection of DOI. The do wn-regulation of cortical 5-HT2A receptor sites in response to a single inj ection of mianserin was accompanied by reductions in 5-HT2A receptor mRNA l evels. Following 4 days of mianserin administration, however, we did not ob serve a change in 5-HT2A receptor mRNA levels, although 5-HT2A receptor den sity was decreased. Thus, changes in receptor mRNA may initially contribute to the down-regulation of 5-HT2A receptors in response to acute mianserin administration. Sustained changes in 5-HT2A receptor mRNA, however, appear not to be involved in maintaining the down-regulation of 5-HT2A receptor nu mber with chronic mianserin administration. Mechanisms other than the regul ation of receptor mRNA levels appear to underlie the down-regulation of 5-M T, receptor sites in response to chronic administration of the agonist DOI. (C) 2000 Elsevier Science Ltd. All rights reserved.