NEUROSTEROID PREGNENOLONE INDUCES SLEEP-EEG CHANGES IN MAN COMPATIBLEWITH INVERSE AGONISTIC GABA-A-RECEPTOR MODULATION

The steroid pregnenolone (P) and its sulfate (PS) can accumulate in th e central nervous system independent of peripheral sources. Pharmacolo gically, the sulphated form of P interacts with the GABA(A) receptor c omplex, and functional assays show that this steroid behaves as an all osteric GABA(A) receptor antagonist. The present study explored the ef fect of a single dose of P upon the sleep-EEG and concurrent secretion of growth hormone and cortisol in male volunteers. P increased the am ount of time spent in slow wave sleep and depressed EEG sigma power. S leep-associated nocturnal cortisol and growth hormone secretion remain ed unchanged, ruling out the possibility that P exerted its effect via altered regulation of these hormones. Furthermore, results from in vi tro studies on the potency of P to activate gene transcription via cor ticosteroid receptors made a genomic action of P via hormone receptor- sensitive DNA sequences unlikely. We conclude that P acts in a non-gen omic fashion at or in the vicinity of the benzodiazepine binding site, modulating allosterically the GABA(A) receptor like a partial inverse agonist.