Functional properties of deoxycorticosterone and spironolactone: molecular characterization and effects on sleep-endocrine activity.
Adrenal steroid hormones are capable of interfering with a variety of behavioral phenomena including sleep. The mechanisms appear to involve effects at the cell membrane as well as nuclear actions mediated by intracellular mineralo- and glucocorticosteroid receptors (MR and GR). We employed the MR agonist deoxycorticosterone (DOC) and the MR antagonist spironolactone (SP) to study the role of MRs in the regulation of human sleep. We also tested whether the effects of DOC upon the sleep EEG and nocturnal hormone secretion (growth hormone and cortisol) are compatible with those predicted for its major metabolite tetrahydro-DOC (THDOC): electrophysiological and animal experiments had suggested that THDOC would act as a hypnotic via positive modulation of the GABAA receptor. Because neither DOC nor SP affected the sleep EEG substantially, the involvement of MRs in the regulation of sleep needs further study. The sleep-endocrine data showed a suppressive effect of DOC upon plasma cortisol concentrations and an earlier occurrence of nocturnal GH maxima, which can be plausibly explained by GR or sigma receptor-mediated effects. Molecular characterization of DOC and SP confirmed a relatively strong effect of DOC upon transactivation via MR and no effect of SP on the GR-mediated transcription rate. In addition, the possibility that a low dose of the mineralocorticoid DOC may serve as a prodrug for the potential hypnotic THDOC is not supported by the current data.
Steiger
A
A
Max Planck Institute of Psychiatry, Department of Psychiatry, Munich, Germany.
Rupprecht
R
R
Spengler
D
D
Guldner
J
J
Hemmeter
U
U
Rothe
B
B
Damm
K
K
Holsboer
F
F
D000328:Adult; D002460:Cell Line; D003900:Desoxycorticosterone / Q000494:pharmacology*; D013006:Growth Hormone / Q000097:blood*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D008297:Male; D009447:Neuroblastoma; D017286:Polysomnography; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000187:drug effects / Q000235:genetics; D012894:Sleep Stages / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013148:Spironolactone / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D003900:Desoxycorticosterone; D013006:Growth Hormone; D006854:Hydrocortisone