Increased 5-HT2A receptor expression and function following central glucocorticoid receptor knockdown in vivo

Central glucocorticoid receptor function may be reduced in depression. In vivo modelling of glucocorticoid receptor underfunctionality would assist in understanding its role in depressive illness. The role of glucocorticoid receptors in modulating 5-HT2A receptor expression and function in the central nervous system (CNS) is presently unclear, but 5-HT2A receptor function also appears altered in depression. With the aid of RNAse H accessibility mapping, we have developed a 21-mer antisense oligodeoxynucleotide (5-TAAAAACAGGCTTCTGATCCT-3', termed GRAS-5) that showed 56% reduction in glucocorticoid receptor mRNA and 80% down-regulation in glucocorticoid receptor protein in rat C-6 glioma cells. Sustained delivery to rat cerebral ventricles in slow release biodegradable polymer microspheres produced a marked decrease in glucocorticoid receptor mRNA and protein in hypothalamus (by 39% and 80%, respectively) and frontal cortex (by 26% and 67%, respectively) 5 days after a single injection, with parallel significant up-regulation of 5-HT2A receptor mRNA expression (13%) and binding (21%) in frontal cortex. 5-HT2A receptor function, determined by DOI-head-shakes, showed a 55% increase. These findings suggest that central 5-HT2A receptors are, directly or indirectly, under tonic inhibitory control by glucocorticoid receptor. (C) 2004 Elsevier B.V. All rights reserved.