Anxiolytic Effects of Indole Alkaloids From Rauvolfia ligustrina in Adult Zebrafish: Involvement of the GABAergic and 5-HT Systems.

Benzodiazepines are widely used in the treatment of anxiety, but their use may be interrupted due to side effects. This study evaluated the indole alkaloids isocarapanaubine (indole alkaloid 1 [AIN1]) and 18-β-hydroxy-3-epi-α-yohimbine (indole alkaloid 2 [AIN2]), extracted from Rauvolfia ligustrina, in adult zebrafish. Three doses (4, 12, and 20 mg/kg) were tested, along with dimethyl sulfoxide (DMSO) 3% and Diazepam (4 mg/kg) in toxicity, locomotion, and anxiolytic effect assays. AIN1 and AIN2 showed low toxicity (lethal dose capable of killing 50% of the animals >20 mg/kg) and reduced locomotor activity. Both exhibited anxiolytic effects, with AIN1 acting through the GABAergic system and AIN2 via the serotonergic pathway (5-HT3A). Interactions with receptors were confirmed by molecular docking, and drug metabolism and pharmacokinetics studies indicated that AIN2 is promising in terms of permeability and safety in the central nervous system.