Ferulic acid methylester improves the comorbidity of insomnia and anxiety in a rat model of PCPA-induced sleep disorder by activating DRN 5-HT neurons.

OBJECTIVE

Previous studies have indicated that ferulic acid possesses sedative and hypnotic functions. As a derivative of ferulic acid, ferulic acid methylester (FAM) exhibits stronger activity and lower toxicity than ferulic acid. This study is intended to establish a rat model of insomnia induced by PCPA, with the aim of exploring the improvement effect of FAM on the comorbidity of anxiety and insomnia in PCPA-induced insomnia model rats and its underlying mechanisms.

METHODS

Insomnia models were established by intraperitoneal injection of 400 mg/kg p-chlorophenylalanine (PCPA) in SD rats. FAM was administered at three doses: 10, 20, and 40 mg/kg. Anxiety levels were assessed using the elevated plus maze and open field tests. Sleep status was evaluated through 24-hour in vivo EEG monitoring. Immunofluorescence staining was used to observe changes in DRN 5-HT neuron activity. Chemogenetic techniques were employed to inhibit DRN 5-HT neurons to elucidate the underlying mechanism.

RESULTS

Behavioral tests revealed that FAM at 20 mg/kg significantly reduced anxiety levels (P < 0.001) and increased total sleep time (P < 0.001). EEG recordings showed improved sleep structure, with increased NREM and REM sleep times. Immunofluorescence staining indicated increased activity of DRN 5-HT neurons following FAM treatment. Chemogenetic inhibition of DRN 5-HT neurons reversed the beneficial effects of FAM on anxiety and sleep, thereby confirming the involvement of these neurons in the mechanism of action of FAM.

CONCLUSIONS

Ferulic acid methylester improves comorbidity of anxiety and insomnia in PCPA-induced insomnia model rats by activating DRN 5-HT neurons.