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 GABA_A 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 GABA_A 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 GABA_A receptor. Both PCA and DZP exhibit comparable amino acid residues with the α3 subunit, suggesting that they bind to similar sites of action.