Allopregnanolone affects sleep in a benzodiazepine-like fashion.
Recent research in rats and humans has shown that exogenous progesterone evokes a sleep profile similar to that induced by agonistic modulators of gamma-aminobutyric acid(A) receptors, such as benzodiazepines. This finding suggests the involvement of the neuroactive metabolite of progesterone, allopregnanolone. In the vehicle-controlled study reported here, we assessed the sleep effects of two doses of allopregnanolone (7.5 and 15 mg/kg), mixed with oil, administered intraperitoneally at light onset in 8 rats. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 postinjection hr. Compared with vehicle, both doses of allopregnanolone reduced the latency to non-rapid eye movement sleep (non-REMS) and 15 mg/kg allopregnanolone significantly increased the time spent in pre-REMS, an intermediate state between non-REMS and REMS. Furthermore, allopregnanolone dose-dependently influenced EEG activity during non-REMS and REMS. In non-REMS, EEG activity was decreased in the lower frequencies (< or =7 Hz) and enhanced in the frequencies of > or =13 Hz. In REMS, allopregnanolone enhanced high-frequency EEG activity (> or =17 Hz). The effects were most pronounced during the first postinjection hours and gradually diminished thereafter. Analysis of the plasma and brain concentrations of allopregnanolone in 45 rats revealed long-lasting increases, which reached maximal levels during the first postinjection hour. The sleep effects of allopregnanolone 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 effects on sleep.
Lancel
M
M
Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany. lancel@mpipsykl.mpg.de
Faulhaber
J
J
Schiffelholz
T
T
Romeo
E
E
Di Michele
F
F
Holsboer
F
F
Rupprecht
R
R
D000704:Analysis of Variance; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D004569:Electroencephalography; D018757:GABA Modulators / Q000494:pharmacology*; D008297:Male; D011280:Pregnanolone / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects; D012890:Sleep / Q000187:drug effects*
D018757:GABA Modulators; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D011280:Pregnanolone