title: Disrupted corticosterone pulsatile patterns attenuate responsiveness to glucocorticoid signaling in rat brain.
abstract: Chronically elevated circulating glucocorticoid levels are although to enhance vulnerability to psychopathology. Here we hypothesized that such sustained glucocorticoid levels, disturbing corticosterone pulsatility, attenuate glucocorticoid receptor signaling and target gene responsiveness to an acute challenge in the rat brain. Rats were implanted with vehicle or 40 or 100% corticosterone pellets known to flatten ultradian and circadian rhythmicity while maintaining daily average levels or mimic pathological conditions. Additionally, recovery from constant exposure was studied in groups that had the pellet removed 24 h prior to the challenge. Molecular markers for receptor responsiveness (receptor levels, nuclear translocation, promoter occupancy, and target gene expression) to an acute challenge mimicking the stress response (3 mg/kg ip) were studied in the hippocampal area. Implantation of 40 and 100% corticosterone pellets dose-dependently down-regulated glucocorticoid receptor and attenuated mineralocorticoid receptor and glucocorticoid receptor translocation to the acute challenge. Interestingly, whereas target gene Gilz expression to the challenge was already attenuated by tonic daily average levels (40%), Sgk-1 was affected only after constant high corticosterone exposure (100%), indicating altered receptor responsiveness due to treatment. Washout of 100% corticosterone recovered all molecular markers (partial), whereas removal of the 40% corticosterone pellet still attenuated responsiveness to the challenge. We propose that corticosteroid pulsatility is crucial in maintaining normal responsiveness to glucocorticoids. Whereas the results with 100% corticosterone are likely attributed to receptor saturation, subtle changes in the pattern of exposure (40%) induces changes at least as severe for glucocorticoid signaling as overt hypercorticism, suggesting an underlying mechanism sensitive to the pattern of hormone exposure.
authors.affiliation: Division of Medical Pharmacology, Leiden/Amsterdam Centre for Drug Research/Leiden University Medical Centre, University of Leiden, Einsteinweg 55, P.O. Box 9502, 2300 RA Leiden, The Netherlands. r.a.sarabdjitsingh@lacdr.leidenuniv.nl
authors.forename: R Angela
authors.initials: RA
authors.lastname: Sarabdjitsingh
authors.forename: Sheena
authors.initials: S
authors.lastname: Isenia
authors.forename: Annelies
authors.initials: A
authors.lastname: Polman
authors.forename: Jona
authors.initials: J
authors.lastname: Mijalkovic
authors.forename: Servane
authors.initials: S
authors.lastname: Lachize
authors.forename: Nicole
authors.initials: N
authors.lastname: Datson
authors.forename: E Ron
authors.initials: ER
authors.lastname: de Kloet
authors.forename: Onno C
authors.initials: OC
authors.lastname: Meijer
mesh_terms: D000204:Activity Cycles; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003345:Corticosterone / Q000008:administration & dosage; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000378:metabolism; D008297:Male; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D003345:Corticosterone; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D014157:Transcription Factors; D000099184:Serum-Glucocorticoid Regulated Kinases; C498609:Tsc22d3 protein, rat