Exploring the impact of MDMA and oxytocin ligands on anxiety and social responses: A comprehensive behavioural and molecular study in the zebrafish model

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Background: Mental disorders, including anxiety and depression, impact nearly 1 billion people worldwide. Recent research has highlighted the potential of certain amphetamine compounds in the therapy of psychiatric disorders, with 3,4-methylenedioxymethamphetamine (MDMA) emerging as a promising candidate. Aim: This study investigates the effects of MDMA on anxiety and social behaviours using 3-week-old zebrafish. Additionally, the role of oxytocin in regulating these behaviours was examined through the use of an oxytocin receptor agonist (WAY-267,464) and antagonist (L-368,899). Methods: Behavioural effects were assessed using the novel exploration test, light–dark preference test and social preference test. To explore the underlying mechanisms, changes in gene expression in serotonin, oxytocin and vasopressin systems and changes in AKT and EKR1/2 signalling pathways were analysed. Results: Acute MDMA exposure reduced thigmotactic behaviour and increased the social preference index, indicating anxiolytic and prosocial effects. However, these effects were biphasic – the lowest tested dose of 0.5 μM showed anxiogenic and prosocial effects. As the concentration increased, these effects reversed, with a peak at 2.5 μM. MDMA suppressed the expression of serotonin receptors ( htr1b and htr2b ) and transporter ( scl6a4 ) genes while increasing oxytocin receptors ( oxtra and oxtrb ) genes, decreasing vasopressin receptor ( avpr1aa ) gene expression, and reducing AKT phosphorylation. The oxytocin receptor agonist mimicked MDMA’s effects, while the antagonist had no significant effect on anxiety or social behaviour. Conclusions: MDMA demonstrates therapeutic potential for treating anxiety disorders and social impairments. Moreover, 3-week-old zebrafish proved to be a valuable model for neurobehavioural research and high-throughput screening of psychiatric treatments.