Exploring zebrafish models of ADHD: A systematic review of genetic and pharmacological approaches

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. Animal models are widely used to investigate the underlying mechanisms of ADHD and evaluate therapeutic interventions. Zebrafish (Danio rerio) have emerged as promising model organisms due to their genetic similarity to humans, rapid development, and suitability for behavioural and pharmacological studies.

To systematically review zebrafish models investigated in ADHD research, focusing on genetic and pharmacological approaches used to model ADHD-related phenotypes, and critically evaluate their behavioural, neurobiological, and pharmacological validity in relation to face, construct, and predictive validity.

A literature search of PubMed, Scopus, and Web of Science databases was conducted up to March 2026 using the search terms "zebrafish" AND ("ADHD" OR "attention-deficit/hyperactivity disorder"). Original research articles investigating zebrafish models of ADHD were included. Studies focusing on unrelated diseases, non-zebrafish models, or drug testing in normal fish were excluded.

13 studies met the inclusion criteria. Both genetic and pharmacological models successfully reproduced key ADHD-like phenotypes, including hyperactivity, impulsivity, attention deficits, and cognitive impairments. Genetic models involving genes such as lphn3.1, adgrl3.1, per1b, micall2b, chmp7, ghrelin, foxp2, syn3, and rbfox1 demonstrated alterations in dopaminergic and GABAergic signaling pathways. Pharmacological models, particularly PFOS exposure, induced behavioural and neurochemical changes consistent with ADHD. Several ADHD-related phenotypes were partially reversed by methylphenidate or atomoxetine, supporting the translational relevance of these models.

Zebrafish provide a robust platform for investigating the genetic, molecular, and environmental mechanisms underlying ADHD. Their suitability for behavioural assessment and high-throughput screening highlights their potential for translational and therapeutic research.