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Concentration, population, and context-dependent effects of AM251 in zebrafish
Steven Tran1, Diptendu Chatterjee2, Amanda Facciol2
1Department of Cell & Systems Biology, University of Toronto, 3359 Mississauga Road North, DV 1022D, Mississauga, Ontario, L5L 1C6, Canada. stevenhuy.tran@mail.utoronto.ca.
Rationale:
The function of the cannabinoid type 1 receptor (CB1-R) is poorly understood in zebrafish, and numerous inconsistent effects have been reported on it in the literature.
Objective:
The objective of the present study is to determine whether differences in the reported effects of CB1-R antagonism on anxiety-like behavioural responses, dopaminergic and serotonergic responses are due to concentration, context-dependent and/or population (genotype-related) effects.
Method:
Two genetically distinct populations of zebrafish (AB and short fin (SF)) were treated with different concentrations of AM251 (0, 0.1, 1mg/L), and behavioural responses were quantified under two different contexts: one, following habituation and two, subsequently in a novel environment. The levels of dopamine, serotonin and their metabolites 3,4-dihydroxyindole acetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) were quantified from whole-brain tissue.
Results:
We demonstrate that a 60-min exposure to AM251 (0, 0.1, 1mg/L) does not alter behavioural performance following habituation in either populations. However, when subsequently transferred to a novel environment, zebrafish that were pre-treated with the highest dose of AM251 (1mg/L) exhibited increased anxiety-like behavioural responses including elevated absolute turn angle, freezing and bottom dwelling. We found that exposure to the highest dose of AM251 (1mg/L) for 60min increased serotonin in fish of both populations tested. In contrast, exposure to 0.1mg/L AM251 decreased, whereas to 1mg/L AM251 increased dopamine, DOPAC and 5-HIAA in fish of both populations.
Conclusion:
Our results demonstrate a genotype-independent effect of AM251 but imply that the inconsistent findings obtained after pharmacological blockade of CB1-Rs in zebrafish may be due to a combination of concentration- and environmental context-dependent effects.
Insights
Cannabinoid type 1 receptor (CB1-R) antagonism in zebrafish causes anxiety-like behaviors and alters neurotransmitter levels, but effects depend on AM251 concentration and environmental context, not genotype.
Area of Science:
- Neuroscience
- Behavioral Pharmacology
- Zebrafish Models
Background:
- The function of cannabinoid type 1 receptor (CB1-R) in zebrafish remains unclear, with conflicting literature reports.
- Understanding CB1-R is crucial for interpreting its role in neurobehavioral regulation.
Purpose of the Study:
- To investigate concentration-dependent and context-specific effects of CB1-R antagonism on zebrafish behavior.
- To determine if genotype influences the response to CB1-R blockade.
- To analyze the impact on dopaminergic and serotonergic systems.
Main Methods:
- Two zebrafish populations (AB and SF) were treated with varying AM251 concentrations (0, 0.1, 1mg/L).
- Behavioral responses were assessed in habituated and novel environments.
- Dopamine, serotonin, and their metabolites (DOPAC, 5-HIAA) were quantified in whole-brain tissue.
Main Results:
- AM251 (1mg/L) induced anxiety-like behaviors (increased freezing, bottom-dwelling) in a novel environment, independent of genotype.
- High-dose AM251 increased serotonin levels.
- Dopamine, DOPAC, and 5-HIAA levels were altered in a dose-dependent manner by AM251.
Conclusions:
- CB1-R antagonism effects in zebrafish are influenced by AM251 concentration and environmental context, not genetic background.
- These findings help reconcile inconsistent results in previous studies on CB1-R function in zebrafish.
