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-HT(2A) receptor expression and function in the central nervous system (CNS) is presently unclear, but 5-HT(2A) 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 C6 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-HT(2A) receptor mRNA expression (13%) and binding (21%) in frontal cortex. 5-HT(2A) receptor function, determined by DOI-head-shakes, showed a 55% increase. These findings suggest that central 5-HT(2A) receptors are, directly or indirectly, under tonic inhibitory control by glucocorticoid receptor.
Islam
Aminul
A
LHS, Aston University, Aston Triangle, Birmingham B4 7ET, UK. islama@nhlbi.nih.gov
Thompson
Kevin S J
KS
Akhtar
Saghir
S
Handley
Sheila L
SL
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D020868:Gene Silencing / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000172:deficiency* / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D016376:Oligonucleotides, Antisense; D044402:Receptor, Serotonin, 5-HT2A; D011965:Receptors, Glucocorticoid