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

Ek, Fredrik LU ; Malo, Marcus; Åberg Andersson, Madelene LU ; Wedding, Christoffer; Kronborg, Joel; Svensson, Peder; Waters, Susanna; Petersson, Per LU and Olsson, Roger LU (2016) In ACS Chemical Neuroscience 7(5). p.46-633
Abstract

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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Journal Article
in
ACS Chemical Neuroscience
volume
7
issue
5
pages
14 pages
publisher
The American Chemical Society
external identifiers
  • scopus:84969872491
  • wos:000376334000013
ISSN
1948-7193
DOI
10.1021/acschemneuro.6b00014
language
English
LU publication?
yes
id
e0c0b4a5-b05f-4593-8fff-32692aef8341
date added to LUP
2016-10-25 21:14:51
date last changed
2017-11-19 04:34:08
@article{e0c0b4a5-b05f-4593-8fff-32692aef8341,
  abstract     = {<p>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.</p>},
  author       = {Ek, Fredrik and Malo, Marcus and Åberg Andersson, Madelene and Wedding, Christoffer and Kronborg, Joel and Svensson, Peder and Waters, Susanna and Petersson, Per and Olsson, Roger},
  issn         = {1948-7193},
  keyword      = {Journal Article},
  language     = {eng},
  month        = {05},
  number       = {5},
  pages        = {46--633},
  publisher    = {The American Chemical Society},
  series       = {ACS Chemical Neuroscience},
  title        = {Behavioral Analysis of Dopaminergic Activation in Zebrafish and Rats Reveals Similar Phenotypes},
  url          = {http://dx.doi.org/10.1021/acschemneuro.6b00014},
  volume       = {7},
  year         = {2016},
}