ALLOPREGNANOLONE AFFECTS SLEEP IN A BENZODIAZEPINE-LIKE FASHION

Recent research in rats and humans has shown that exogenous progestero ne evokes a sleep profile similar to that induced by agonistic modulat ors of gamma-aminobutyric acid(A) receptors, such as benzodiazepines. This finding suggests the involvement oi the neuroactive metabolite of progesterone, allopregnanolone. In the vehicle-controlled study repor ted here, we assessed the sleep effects of two doses of allopregnanolo ne (7.5 and 15 mg/kg), mixed with oil, administered intraperitoneally at light onset in 8 rats. The electroencephalogram (EEG) and electromy ogram were recorded during the first 6 postinjection hr. Compared with vehicle, both doses of allopregnanolone reduced the latency to non-ra pid eye movement sleep (non-REMS) and 15 mg/kg allopregnanolone signif icantly increased the time spent in pre-REMS, an intermediate state be tween non-REMS and REMS. Furthermore, allopregnanolone dose-dependentl y influenced EEG activity during non-REMS and REMS. In non-REMS, EEG a ctivity was decreased in the lower frequencies (less than or equal to 7 Hz) and enhanced in the frequencies of greater than or equal to 13 H z. In REMS, allopregnanolone enhanced high-frequency EEG activity (gre ater than or equal to 17 Hz). The effects were most pronounced during the first postinjection hours and gradually diminished thereafter. Ana lysis of the plasma and brain concentrations of allopregnanolone in 45 rats revealed long-lasting increases, which reached maximal levels du ring the first postinjection hour. The sleep effects of allopregnanolo ne are very similar to those elicited by larger doses of progesterone, which produce comparable brain levels of allopregnanolone. These data indicate that the steroid allopregnanolone has benzodiazepine-like ef fects on sleep.