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[Display omitted] • Fermented Perilla frutescens var. acuta (FPF) has a sleep-promoting effect. • FPF increases neuronal activity in sleep-promoting brain regions. • FPF decreases neuronal activity in wake-promoting brain regions. • FPF has a direct binding and agonistic activity for adenosine A 1 receptor (A 1 R). Perilla frutescens (PF) is a plant with various biological activities, including antioxidant and antidepressant activities; however, the efficacy of its fermented product has not been evaluated. Herein, we found that the Bacillus subtilis -fermented PF (FPF) increased non-rapid eye movement sleep and slow wave activity. FPF improved the sleep onset latency and sleep duration in a pentobarbital-induced sleep model, and this efficacy was abolished by the adenosine A 1 receptor (A 1 R) antagonist. In addition, FPF increased and decreased the neuronal activity in sleep-activating and inhibiting brain regions, respectively, and these effects were also blocked by A 1 R antagonist 8-cyclopentyl-1,3-dipropylxanthine. Furthermore, FPF exhibited direct binding and agonistic activities for A 1 R. HPLC/NMR analysis revealed uracil, protocatechuic acid, apigenin-7-O-diglucuronide, and luteolin-7-O-glucuronide to be the major active components responsible for the sleep-promoting efficacy of FPF. In conclusion, this study suggests that FPF has A 1 R agonistic activity and this novel activity may be critical for its sleep-promoting effect. [ABSTRACT FROM AUTHOR]