Anxiolytic-like effects of p-coumaric acid via GABAergic interaction pathways: an in vivo and in silico study.

p-Coumaric acid (PCA) is a naturally occurring phenolic compound widely distributed in plants, known for its antioxidant, anti-inflammatory, and antimicrobial properties. The present study's objective was to perform behavioral tests and in silico molecular docking with GABAA receptor subunits to examine the anxiolytic effect of PCA and assess its underlying mechanism. PCA was administered orally at dosages of 25 mg/kg and 50 mg/kg individually or in combination to Swiss albino mice. We used the GABAergic agonist diazepam (DZP-1 mg/kg) and the antagonist flumazenil (FLU-0.1 mg/kg) as positive controls and the vehicle (distilled water) as the negative control group in order to evaluate its potential anxiolytic effect. We also used a variety of behavioral techniques such as open field, swing box, hole cross, and dark-light tests. Additionally, molecular docking was used to analyze the binding affinities of PCA, DZP, and FLU toward the GABAA receptor (α2 and α3 subunits), which are connected to the anxiolytic effect. Swiss albino mice treated with PCA at higher dosages (PCA-50 mg/kg) exhibited notable anxiolytic-like effects. Combining PCA-50 with DZP and FLU resulted in greater anxiolytic effects than each group separately, indicating potential antagonistic and synergistic effects for anxiety disorders. Additionally, PCA exhibited highest binding affinity (- 5.4 kcal/mol) and generated several hydrogen and hydrophobic bonds with the α3 subunit of the GABAA receptor. Both PCA and DZP exhibit comparable amino acid residues with the α3 subunit, suggesting that they bind to similar sites of action.