Behavioral Analysis of Dopaminergic Activation in Zebrafish and Rats Reveals Similar Phenotypes

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• 作者：Fredrik Ek ; Marcus Malo ; Madelene Åberg Andersson ; Christoffer Wedding ; Joel Kronborg ; Peder Svensson ; Susanna Waters ; Per Petersson ; Roger Olsson
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：May 18, 2016
• 年：2016
• 卷：7
• 期：5
• 页码：633-646
• 全文大小：832K
• 年卷期：0
• ISSN：1948-7193

文摘

Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300–3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose–response relationship in the variable distance traveled. In this study, we focused on breaking down distance traveled into more detailed behavioral phenotypes for both zebrafish and rats and identified in the multivariate analysis low and high dose phenotypes with characteristic behavioral features. Further analysis of single parameters also identified an increased activity at the lowest concentration indicative of a U-shaped dose–response. Apomorphine increased the distance of each swim movement (bout) at both high and low doses, but the underlying behavior of this increase is different; at high dose, both bout duration and frequency increased whereas bout max speed was higher at low dose. Larvae also displayed differences in place preference. The low dose phenotype spent more time in the center, indicative of an anxiolytic effect, while the high-dose phenotype had a wall preference. These dose-dependent effects corroborated findings in a parallel rat study and previous observations in humans. The translational value of pharmacological zebrafish studies was further evaluated by comparing the amino acid sequence of the dopamine receptors (D₁–D₄), between zebrafish, rats and humans. Humans and zebrafish share 100% of the amino acids in the binding site for D₁ and D₃ whereas D₂ and D₄ receptors share 85–95%. Molecular modeling of dopamine D₂ and D₄ receptors indicated that nonconserved amino acids have limited influence on important ligand–receptor interactions.