Regulation of 5-HT_2A receptor mRNA levels and binding sites in rat frontal cortex by the agonist DOI and the antagonist mianserin

In the present study we have characterized the time course of effect of administration of the serotonin₂ (5-HT₂) receptor antagonist mianserin, or the 5-HT₂ receptor agonist (±)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), on 5-HT_2A receptor binding sites and mRNA levels in rat frontal cortex. Radioligand binding and ribonuclease protection assays were performed with separate hemispheres of frontal cortex from each animal to examine concomitant changes in 5-HT_2A receptor sites and mRNA levels. The decrease in cortical 5-HT_2A receptor sites in response to chronic DOI administration was not accompanied by changes in 5-HT_2A receptor mRNA. A single injection of DOI produced a transient decrease in 5-HT_2A receptor mRNA levels detected 1 h post-injection. The density of 5-HT_2A receptor sites, however, was not significantly reduced following a single injection of DOI. The down- regulation of cortical 5-HT_2A receptor sites in response to a single injection of mianserin was accompanied by reductions in 5-HT_2A receptor mRNA levels. Following 4 days of mianserin administration, however, we did not observe a change in 5-HT_2A receptor mRNA levels, although 5-HT_2A receptor density was decreased. Thus, changes in receptor mRNA may initially contribute to the down-regulation of 5-HT(2A) receptors in response to acute mianserin administration. Sustained changes in 5-HT_2A receptor mRNA, however, appear not to be involved in maintaining the down-regulation of 5- HT_2A receptor number with chronic mianserin administration. Mechanisms other than the regulation of receptor mRNA levels appear to underlie the down-regulation of 5-HT_2A receptor sites in response to chronic administration of the agonist DOI.