# Serotonergic Neuromodulation of Natural Products Isoreserpine and Isoreserpiline in Adult Zebrafish: An in Silico and In Vivo Investigation

## TL;DR

This study explores the anxiolytic effects of two natural compounds in zebrafish, finding one to be a promising alternative to benzodiazepines.

## Contribution

The study identifies isoreserpiline as a novel compound with strong serotonergic anxiolytic potential and favorable pharmacokinetic properties.

## Key findings

- Isoreserpiline (IRPL) showed higher affinity for the 5-HT3AR receptor compared to isoreserpine (IRPN).
- IRPL exhibited better absorption and central nervous system penetration properties.
- Anxiolytic effects were reversed by granisetron, indicating serotonergic involvement.

## Abstract

Anxiety is a multidimensional behavioral disorder widely studied in neuroscience due to the involvement of specific neural circuits. Although benzodiazepines are commonly used, their side effects drive the search for new therapeutic alternatives. This study investigated the anxiolytic effects of the indole alkaloids isoreserpine (IRPN) and isoreserpiline (IRPL), extracted from Rauvolfia ligustrina, in adult zebrafish at doses of 4, 12, and 20 mg/kg, along with 3% DMSO and diazepam (4 mg/kg) as controls. Toxicity, locomotor activity, anxiolytic effects, and serotonergic involvement were assessed. Interactions with the 5‐HT3AR receptor were analyzed through molecular docking, and pharmacokinetic properties were evaluated using DMPK. The samples showed no toxicity (LD50 > 20 mg/kg), reduced locomotor activity, and exhibited anxiolytic effects that were reversed by granisetron. IRPL demonstrated higher affinity for the 5‐HT3AR receptor and better absorption and central nervous system penetration properties, standing out as a promising candidate for the treatment of anxiety.