THC causes repetitive swimming in zebrafish that mirrors psychosis-like behavior | Research

The takeaway

THC induced concentration-dependent repetitive circular swimming in zebrafish, a behavior that was reduced by NMDA receptor activation and the antipsychotic sulpiride, suggesting a new animal model for studying cannabis-psychosis mechanisms.

Neuroscience researchers, psychosis mechanism investigators, pharmacologists studying cannabinoid receptors

CB1 inverse agonist did not block THC-induced stereotypy, but CB2 inverse agonist did

What the researchers found

THC caused dose-dependent behavioral stereotypy (repetitive circular swimming) in adult zebrafish. This behavior was reduced by co-administration of NMDA, the antipsychotic sulpiride, and the cannabinoid receptor 2 inverse agonist AM630, but was not blocked by the cannabinoid receptor 1 inverse agonist AM251.

Why it matters

Understanding the biological mechanisms connecting THC to psychosis requires accessible animal models. This zebrafish model offers a rapid, cost-effective platform for testing potential interventions and dissecting the receptor pathways involved.

The numbers in context

Concentration-dependent THC response measured via novel Repetition Index; NMDA co-administration reduced stereotypy; AM251 (CB1 inverse agonist) did not block the effect; AM630 (CB2 inverse agonist) significantly reduced it; sulpiride (antipsychotic) also reduced it

How the study worked

Adult zebrafish were exposed to varying THC concentrations, and a novel Repetition Index was developed to quantify circular swimming behavior. Co-administration experiments tested the involvement of NMDA receptors, GABA receptors, cannabinoid receptors 1 and 2, and the antipsychotic sulpiride.

What this study cannot tell us

Animal model with limited translational certainty to human psychosis. Zebrafish behavior is a simplified proxy for complex human psychiatric phenomena. Acute exposure only; does not model chronic use patterns.

How to read the evidence

Novel animal model with interesting mechanistic findings, but preliminary and not yet validated against human outcomes.

When this study was published

Published in 2021.

The bigger picture

The finding that THC-induced psychosis-like behavior may be CB1-independent but CB2-dependent challenges conventional thinking about cannabinoid receptor involvement in psychosis and could redirect therapeutic development efforts.

Questions still open

If the psychosis-like effect is CB1-independent, what does that mean for current theories about THC and psychosis risk? Could CB2 receptor modulation become a therapeutic target?

Common questions

Why use zebrafish to study THC and psychosis?

Zebrafish have a conserved endocannabinoid system and allow rapid, cost-effective screening of drug interactions. THC-induced repetitive behavior in zebrafish parallels stereotypy seen in rats exposed to THC and psychotropic drugs like ketamine.

What was surprising about the receptor findings?

The psychosis-like behavior persisted when CB1 receptors were blocked but was reduced when CB2 receptors were blocked, suggesting CB2 may play a larger role in THC-induced psychosis-like effects than previously recognized.

Read the original research

THC-induced behavioral stereotypy in zebrafish as a model of psychosis-like behavior.

Scientific reports, 11(1), 15693

View on PubMed ↗Publisher’s paper ↗

Citation

Dahlén, Amelia; Zarei, Mahdi; Melgoza, Adam; Wagle, Mahendra; Guo, Su. (2021). THC-induced behavioral stereotypy in zebrafish as a model of psychosis-like behavior.. Scientific reports, 11(1), 15693. https://doi.org/10.1038/s41598-021-95016-4