REGIONAL VARIABILITY IN CHANGES IN 5-HT2A RECEPTOR MESSENGER-RNA LEVELS IN RAT-BRAIN FOLLOWING IRREVERSIBLE INACTIVATION WITH EEDQ

In this study, the relationship between the expression of 5-HT2A recep tors and level of 5-HT2A receptor mRNA in discrete regions of rat brai n was examined by inactivating 5-HT2A receptors with the alkylating ag ent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 10 mg/kg, i. p.) and measuring the time course of receptor recovery and changes in mRNA levels. In untreated controls, the distribution and levels of 5-H T2A receptors labeled with [H-3]ketanserin and receptor mRNA labeled w ith a 230-base P-33-labeled riboprobe were found to be highly correlat ed in most sub-regions of the cortex, the caudate-putamen and the clau strum but not in the piriform cortex or the hippocampus. Administratio n of EEDQ produced 90-99% inactivation of 5-HT2A receptors and the rat e of receptor recovery was uniform in most regions studied. 5-HT2A rec eptors in most regions reached control levels by day 14, the lone exce ption being the caudate-putamen where receptors reached only 56% of co ntrol by day 14. Following inactivation of receptors with EEDQ there w as a transient increase in levels of 5-HT2A receptor mRNA in several r egions. Although rates of receptor recovery were uniform, four distinc t patterns of mRNA response were observed: (1) early elevation followe d by late elevation, (2) early elevation only, (3) late elevation only , and (4) no detectable change. The absence of a direct relationship b etween changes in 5-HT2A receptor mRNA and 5-HT2A receptor recovery in this model system suggests that transcriptional regulation is not the mechanism controlling the recovery of these receptors after irreversi ble inactivation. This study also lends support to the idea that alter native mechanisms may play a role in 5-HT2A receptor regulation after other pharmacological and physiological manipulations. The regional va riability in 5-HT2A mRNA regulation reported here highlights the impor tance of using techniques with a high level of anatomical resolution t o study changes in 5-HT2A receptor mRNA levels.