Progesterone induces changes in sleep comparable to those of agonistic GABA(A) receptor modulators

There is much evidence that progesterone has hypnotic anesthetic properties. In this vehicle-controlled study, we examined the effects of three doses of progesterone (30, 90, and 180 mg/kg) administered intraperitoneally at light onset on sleep in rats. Progesterone dose dependently shortened non-rapid eye movement sleep (NREMS) latency, lengthened rapid eye movement sleep (REMS) latency, decreased the amount of wakefulness and REMS, and markedly increased pre-REMS, an intermediate state between NREMS and REMS. Progesterone also elicited dose-related changes in sleep state-specific electroencephalogram (EEG) power densities. Within NREMS, EEG activity was reduced in the lower frequencies (≤7 Hz) and was enhanced in the higher frequencies. Within REMS, EEG activity was markedly enhanced in the higher frequencies. The effects were maximal during the first postinjection hours. The concentrations of progesterone and the progesterone metabolites 3α-hydroxy-5α-pregnan-20-one and 3α-hydroxy-5β-pregnan-20- one, both positive allosteric modulators of γ-aminobutyric acid A (GABA(A)) receptors, were determined at different time intervals after vehicle and 30 or 90 mg/kg progesterone. Progesterone administration resulted in dose- dependent initially supraphysiological elevations of progesterone and its metabolites in the plasma and brain, which were most prominent during the first hour postinjection. The effects of progesterone on sleep closely resemble those of agonistic modulators of GABA(A) receptors such as benzodiazepines and correlate well with the increases in the levels of its GABA(A) agonistic metabolites. These observations suggest that the hypnotic effects of progesterone are mediated by the facilitating action of its neuroactive metabolites on GABA(A) receptor functioning.