Neurosteroid pregnenolone induces sleep-EEG changes in man compatible with inverse agonistic GABAA-receptor modulation.
The steroid pregnenolone (P) and its sulfate (PS) can accumulate in the central nervous system independent of peripheral sources. Pharmacologically, the sulphated form of P interacts with the GABAA receptor complex, and functional assays show that this steroid behaves as an allosteric GABAA receptor antagonist. The present study explored the effect of a single dose of P upon the sleep-EEG and concurrent secretion of growth hormone and cortisol in male volunteers. P increased the amount of time spent in slow wave sleep and depressed EEG sigma power. Sleep-associated nocturnal cortisol and growth hormone secretion remained unchanged, ruling out the possibility that P exerted its effect via altered regulation of these hormones. Furthermore, results from in vitro studies on the potency of P to activate gene transcription via corticosteroid receptors made a genomic action of P via hormone receptor-sensitive DNA sequences unlikely. We conclude that P acts in a non-genomic fashion at or in the vicinity of the benzodiazepine binding site, modulating allosterically the GABAA receptor like a partial inverse.
Steiger
A
A
Max Planck Institute of Psychiatry, Department of Psychiatry, Munich, Germany.
Trachsel
L
L
Guldner
J
J
Hemmeter
U
U
Rothe
B
B
Rupprecht
R
R
Vedder
H
H
Holsboer
F
F
D000328:Adult; D000732:Androstanols / Q000494:pharmacology; D004569:Electroencephalography; D013006:Growth Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D011284:Pregnenolone / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000502:physiology*; D012890:Sleep / Q000187:drug effects*
D000732:Androstanols; D011963:Receptors, GABA-A; C018370:pregnenolone sulfate; D011284:Pregnenolone; C049154:11,17-dihydroxy-6-methyl-17-(1-propynyl)androsta-1,4,6-triene-3-one; D013006:Growth Hormone; D006854:Hydrocortisone