Differential effects of the novel neurosteroid hypnotic (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile on electroencephalogram activity in male and female rats

Background We recently showed that a neurosteroid analogue, (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH), induced hypnosis in rats. The aim of the present study was to evaluate the hypnotic and anaesthetic potential of 3β-OH further using electroencephalography. Methods We used behavioural assessment and cortical electroencephalogram (EEG) spectral power analysis to examine hypnotic and anaesthetic effects of 3β-OH (30 and 60 mg kg −1 ) administered intraperitoneally or intravenously to young adult male and female rats. Results We found dose-dependent sex differences in 3β-OH-induced hypnosis and EEG changes. Both male and female rats responded similarly to i.p. 3β-OH 30 mg kg −1 . However, at the higher dose (60 mg kg −1 , i.p.), female rats had two-fold longer duration of spontaneous immobility than male rats (203.4 [61.6] min vs 101.3 [32.1] min), and their EEG was suppressed in the low-frequency range (2–6 Hz), in contrast to male rats. Although a sex-dependent hypnotic effect was not confirmed after 30 mg kg −1 i.v., female rats appeared more sensitive to 3β-OH with relatively small changes within delta (1–4 Hz) and alpha (8–13 Hz) bands. Finally, 3β-OH had a rapid onset of action and potent hypnotic/anaesthetic effect after 60 mg kg −1 i.v. in rats of both sexes; however, all female rats and only half of the male rats reached burst suppression, an EEG pattern usually associated with profound inhibition of thalamocortical networks. Conclusions Based on its behavioural effects and EEG signature, 3β-OH is a potent hypnotic in rats, with female rats being more sensitive than male rats.