PROGESTERONE INDUCES CHANGES IN SLEEP COMPARABLE TO THOSE OF AGONISTIC GABA(A) RECEPTOR MODULATORS

There is much evidence that progesterone has hypnotic anesthetic prope rties. In this vehicle-controlled study, we examined the effects of th ree doses of progesterone (30, 90, and 180 mg/kg) administered intrape ritoneally at light onset on sleep in rats. Progesterone dose dependen tly shortened non-rapid eye movement sleep (NREMS) latency, lengthened rapid eye movement sleep (REMS) latency, decreased the amount of wake fulness and REMS, and markedly increased pre-REMS, an intermediate sta te between NREMS and REMS. Progesterone also elicited dose-related cha nges in sleep state-specific electroencephalogram (EEG) power densitie s. Within NREMS, EEG activity was reduced in the lower frequencies (le ss than or equal to 7 Hz) and was enhanced in the higher frequencies. Within REMS, EEG activity was markedly enhanced in the higher frequenc ies. The effects were maximal during the first postinjection hours. Th e concentrations of progesterone and the progesterone metabolites 3 al pha-hydroxy-5 alpha-pregnan-20-one and 3 alpha-hydroxy-5 beta-pregnan- 20-one, both positive allosteric modulators of gamma-aminobutyric acid A (GABA(A)) receptors, were determined at different time intervals af ter vehicle and 30 or 90 mg/kg progesterone. Progesterone administrati on resulted in dose-dependent initially supraphysiological elevations of progesterone and its metabolites in the plasma and brain, which wer e most prominent during the first hour postinjection. The effects of p rogesterone 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 o bservations suggest that the hypnotic effects of progesterone are medi ated by the facilitating action of its neuroactive metabolites on GABA (A) receptor functioning.