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118during the physiological sleep-wake cycle in mice. These effects were thought to be obtained by nega-tively modulating the activities of GABA and glycine at GABAA and glycine receptors, respec-tively2).Effects of sake yeast on sleep promotion in mice with stress-induced acute insomniaConventional benzodiazepines, non-benzodiaze-pine receptor agonists, and orexin receptor antagonists are used in general clinical practice for drug treatment of insomnia. However, there are well-known adverse risks associated with the use of benzodiazepines and non-benzodiazepines sedatives, including toler-ance, addiction, abuse, and paradoxical reactions such as aggression, violence, and impulsivity. In addition, the use of benzodiazepines and non-ben-zodiazepines has been associated with an increased risk of falls, fractures, and cognitive impairment in the elderly.sedative-hypnotics, melatonin Recent studies have shown that several natural compounds that focus on adenosine receptor (AR) activation can have sleep-promoting effects. Previous studies have shown that sake yeast is a dose-dependent adenosine A2A receptor (A2AR) agonist that promotes NREM sleep by accumu-lating S-adenosylmethionine or methylthioadenosine during wakefulness in mice. Similarly, some previous studies have demonstrated that sake yeast can improve sleep quality in humans. Based on these previous studies, in the present study we tested the sleep-inducing effects of sake yeast in mice under an acute insomnia model.In this study, we evaluated the effects of sake yeast, an adenosine analogue, on sleep-wake stage, locomotion, and core body temperature in a stressful environment as a model of acute insomnia using sleep EEG, electromyography, and telemetry implants in mice. We have already verified in previous experiments that a novel environment in which mice in the sleep phase are transferred from habituated cages to new cages is useful as a model for acute insomnia5). In the present study, two different doses of sake yeast (200 mg/kg and 300 mg/kg) and vehicle without sake yeast at ZT2 on different days were orally administered to mice removed from habituated cages and then trans-ferred to new cages. 1) Nishimon S, Nishimon M, Nishino S: Tasimelteon for treating non-24-h sleep-wake rhythm disorder. Expert Opin Pharmacother, 2019; 20: 1065-1073. 2) Nishimon S, Yamaguchi M, Muraki H, et al: Intraperi-As a result, we showed that sake yeast dose-de-pendently increased REM and non-REM sleep, decreased arousal within 6 hours after oral admin-istration of sake yeast, and decreased locomotion and core body temperature in a new cage. These results indicate that sake yeast may induce sleep even under conditions of acute insomnia via activa-tion of A2AR. In the future, it will be interesting to investigate the potential involvement of adenosine in the pathophysiology of insomnia4).We found that ginkgolide B dose-dependently increased the amount of arousal and decreased the amount of NREM sleep in mice. We also showed that sake yeast regulates locomotion and thermo-regulation and promotes both REM and NREM sleep in acute insomnia via activation of A2AR. Understanding the mechanisms by which these natural compounds induce wakefulness or sleep effects may provide an opportunity to develop new therapeutic agents. However, in both studies, there have been no comparative studies with existing synthetic drugs that have wakefulness- or sleep-in-ducing effects, and further validation is desirable.The author would like to greatly appreciate the Juntendo Scholarship Program of the Graduate Association. The author would also like to greatly appreciate Professor Seiji Nishino in Stanford University and Professor Heii Arai in Juntendo University for providing me with this opportunity.No funding was received.SN drafted the report, and contributed to and have approved the final manuscript.The author declares that there are no conflicts of interest.ConclusionAcknowledgmentsFundingAuthor contributionsConflicts of interest statementReferences