Succinic acid enhances sedative activity of diazepam through GABAergic receptor modulation: Evidence from behavioral...

Insomnia, a widespread neurological condition, is often managed with diazepam (DZP), a gamma-aminobutyric acid A (GABA_A) receptor agonist, though prolonged use raises concerns about dependence and cognitive impairment. This study investigated the sedative and locomotor-suppressive effects of succinic acid (SUC), alone and in combination with DZP, supported by behavioral and computational analyses. Swiss albino mice were treated intraperitoneally (i.p.) with SUC (5, 10, 15 mg/kg), DZP (2 mg/kg), and their combination (SUC 10 + DZP 2 mg/kg), followed by thiopental sodium (TS)-induced sleep and locomotor activity tests. SUC significantly reduced sleep latency and extended sleep duration in a dose-dependent manner, with the combination group showing the most potent synergistic effect (sleep duration: 185.14 ± 2.73 min). In the open-field and light-dark tests, SUC suppressed locomotor activity and enhanced dark residence time (DRT), further confirming central nervous system (CNS) depressant effects. In silico docking to the GABA_A receptor (PDB: 6X3X) revealed that SUC, despite having lower binding affinity (-4.1 kcal/mol) than DZP (-8.4 kcal/mol), formed more hydrogen bonds with key residues, suggesting stable and supportive receptor engagement. Pharmacokinetic (PK) profiling showed SUC is highly water-soluble, moderately absorbed (71.75%), poorly blood-brain barrier (BBB)-penetrant, and exhibits low toxicity (lethal dose 50 (LD₅₀) = 2260 mg/kg). These findings support SUC's potential as a safe, effective sedative agent, capable of enhancing DZP efficacy while possibly reducing its side effects. Future directions include exploring SUC derivatives with better brain penetration and validating these effects in clinical models.