Maybe this is piece of the puzzle. If this is already known then my apologies.
The following is from a paper showing a Japanese traditional medicine alleviates insomnia and increases sleep duration via ALLO production through upregulation of SRD5A1 in the olfactory bulb.
Abstract
Yokukansankachimpihange (YKSCH), a traditional Japanese medicine composed of 9 crude drugs, is designed to improve neurosis, insomnia in adults, and night crying in children.
YKSCH has been reported to improve diurnal rhythm in patients with Alzheimerās disease and prolong the total sleeping time in healthy subjects. However, little is known about how YKSCH alleviates sleep disorders. Here, we investigated whether and how YKSCH treatment affected sleep latency and duration in group-housed and socially isolated mice.
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Male ddy mice were treated with YKSCH [1,500 mg/kg, per os (p.o.)] in group-housed or socially isolated conditions for 3ā4 weeks. After the last injection, mice were intraperitoneally (i.p.) administered with pentobarbital (60 mg/kg) and the sleep latency and duration was evaluated. The results show that pretreatment with YKSCH had no effect on sleep latency or duration in group-housed mice. However, YKSCH treatment significantly improved the reduced sleep duration in socially isolated mice. This effect of YKSCH was inhibited by the administration of bicuculline (3 mg/kg, i.p.), a GABAA receptor antagonist. Furthermore, we showed that YKSCH treatment improved the decrease in allopregnanolone content and its synthase expression levels in the olfactory bulb. These results suggest that YKSCH treatment improved social isolation stress-induced insomnia via the GABAergic pathway and that the mechanism of action of YKSCH is partly due to improvement of allopregnanolone levels of expression.
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Several reports have shown that social isolation stress-induced behavioral abnormalities are related to the reduction in ALLO contents in the OB and PFC (22). The ALLO content is reported to be about twice higher in the OB than that in PFC (22). Olfactory dysfunction is frequently observed in patients with REM sleep behavior disorders, such as dementia and Parkinsonās disease (34, 35). In addition, some reports have shown that olfactory bulbectomy in rats induces a reduction in REM sleep duration and frequency (36). These reports suggest that the OB has an important role in sleep-wakefulness patterns. Biosynthesis of ALLO in the brain is regulated by two specific enzymes. It starts with the conversion of progesterone into 5Ī±-dihydroprogesterone by the SRD5A1 enzyme. Next, 5Ī±-dihydroprogesterone is converted into ALLO by the 3Ī±-HSD enzyme. Social isolation stress does not change the brainās content of progesterone and pregnenolone (29). In socially isolated mice, brain expression of SRD5A1 mRNA and protein was approximately 50% less than in group-housed mice, whereas the expression of 3Ī±-HSD mRNA was unchanged (19). These reports suggest SRD5A1 is the enzyme responsible for producing the brain ALLO in this model. Here, we demonstrated that YKSCH treatment inhibited the decrease in both ALLO content and SRD5A1 expression levels in the OB
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Brain cells synthesize ALLO from progesterone by two types enzymes, SRD5A1 and 3Ī±-hydroxysteroid oxidoreductase. In socially isolated mice, the expression level of SRD5A1 is reduced in the OB and PFC, but 3Ī±-hydroxysteroid oxidoreductase is unaffected (19). This report indicates that SRD5A1 is responsible for producing ALLO in this model. In this study, we investigated whether YKSCH treatment affected the SRD5A1 expression level in the OB and PFC. As a result, YKSCH treatment improved the reduction of SRD5A1 expression levels in the OB.
