Sedative and hypnotic effects of nuciferine: enhancing rodent sleep via serotonergic system modulation.

BACKGROUND: Insomnia is the most prevalent sleep disorder globally. Nuciferine (NF), a bioactive constituent extracted from Nelumbo nucifera leaves, is recognized for its diverse pharmacological activities. However, its sleep-regulating effects have not been investigated. This study aimed to delineate the therapeutic effects and underlying mechanisms of NF in mitigating insomnia. METHODS: The sedative-hypnotic effects of NF were assessed employing locomotor activity test, pentobarbital-induced sleep test, and electroencephalography-based sleep profiling. Insomnia symptoms in rodents were induced by serotonin (5-HT) depletion and environmental stress. The potential mechanisms of NF's action through the regulation of central serotonin system were also explored. RESULTS: Nuciferine attenuated locomotor activity and extended pentobarbital-induced sleep duration in a dose-dependent manner. It also significantly augmented total and non-rapid eye movement (NREM) sleep time and enhanced delta power at frequencies of 0.5 and 1 Hz in normal rats. Sleep analysis revealed that NF effectively reversed the reduction in total and NREM sleep time caused by environmental stress from cage changing. NF treatment also proved effective against insomnia induced by 5-HT depletion, as evidenced by increased sleep duration and reduced sleep latency. Further investigation revealed a synergetic effect of NF and 5-hydroxytryptophan, alone with increased 5-HT and 5-HT1A receptor levels in the hypothalamus of insomniac mice following NF administration. CONCLUSIONS: The results demonstrate NF's hypnotic effects and its ability to alleviate insomnia, providing preclinical evidence for its potential as a naturally derived treatment for insomnia.