Ferulic acid alleviates abnormal behaviors in isolation-reared mice via 5-HT1A receptor partial agonist activity

Abstract

Rationale: Preclinical and clinical reports suggest that ferulic acid (FA), a plant-derived phenylpropanoid, is effective against mental health problems such as agitation, anxiety, and irritability in humans, without causing adverse side effects. However, the mechanism of action is unknown.

Objective: The aim of the study is to investigate the mechanism underlying the ameliorative effects of FA on mental health problems such as agitation, anxiety, and irritability, using in vivo behavioral analysis, in vitro pharmacological analysis, and in silico binding analysis.

Methods: The effects of FA (10 mg/kg, 50 mg/kg, and 250 mg/kg) on hyperactivity and aggressive behaviors of isolation-reared mice were examined. The effects of FA (50 mg/kg and 250 mg/kg) on extracellular levels of monoamines such as serotonin (5-HT), dopamine, and noradrenaline were analyzed by in vivo microdialysis. The effects of FA (10^-13-10^-6 M) on 5-HT_1A and 5-HT_2A receptors were analyzed using a luciferase reporter gene assay. Binding of FA to the mouse 5-HT_1A receptor was evaluated by in silico analysis.

Results: The behavioral analysis showed that administration of FA (50 mg/kg) 1 h before experiments significantly alleviated hyperactivity and aggressive behaviors in isolation-reared mice. These alleviative effects were abolished by pretreatment with the 5-HT_1A receptor antagonist WAY-100635 (1 mg/kg). In vivo microdialysis analysis showed that FA (50 mg/kg) did not change extracellular monoamine levels in the prefrontal cortex of mice. The luciferase reporter gene assay indicated that FA activated 5-HT_1A receptors, but not 5-HT_2A receptors, in a dose-dependent manner. The maximal response of 5-HT_1A receptors to FA was weaker than that to 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), a 5-HT_1A receptor full agonist. In silico binding analysis showed that FA binds to the orthosteric site of 5-HT_1A receptors.

Conclusion: Taken together, these results suggest that FA ameliorates agitation-, anxiety-, and irritability-like behaviors such as hyperactivity and aggressive behaviors in isolation-reared mice via 5-HT_1A receptor partial agonist activity. These findings support the efficacy of FA on mental health problems that have been suggested in preclinical and clinical practice.

Keywords: 5-HT1A receptor; Abnormal behavior; Ferulic acid; Isolation-reared mice; Partial agonist.