PUBLICATION
Zebrafish larvae are insensitive to stimulation by cocaine: importance of exposure route and toxicokinetics
- Authors
- Kirla, K.T., Groh, K.J., Steuer, A.E., Poetzsch, M., Banote, R.K., Stadnicka-Michalak, J., Eggen, R.I., Schirmer, K., Kraemer, T.
- ID
- ZDB-PUB-160816-10
- Date
- 2016
- Source
- Toxicological sciences : an official journal of the Society of Toxicology 154(1): 183-193 (Journal)
- Registered Authors
- Kirla, Krishna Tulasi
- Keywords
- LC-MS/MS and MALDI imaging, cocaine, distribution, locomotor activity, zebrafish
- MeSH Terms
-
- Animals
- Cocaine/administration & dosage*
- Cocaine/pharmacokinetics*
- Embryo, Nonmammalian/drug effects*
- Gills
- Larva/drug effects*
- Skin
- Toxicokinetics*
- Zebrafish
- PubMed
- 27521082 Full text @ Toxicol. Sci.
Citation
Kirla, K.T., Groh, K.J., Steuer, A.E., Poetzsch, M., Banote, R.K., Stadnicka-Michalak, J., Eggen, R.I., Schirmer, K., Kraemer, T. (2016) Zebrafish larvae are insensitive to stimulation by cocaine: importance of exposure route and toxicokinetics. Toxicological sciences : an official journal of the Society of Toxicology. 154(1):183-193.
Abstract
Zebrafish (Danio rerio) larvae have been suggested as vertebrate model to complement or even replace mammals for rapidly assessing behavioral effects of psychoactive drugs. Yet, divergent responses have been reported in mammals and fish despite the conservation of many drug targets. Cocaine, for example, acts as stimulant in mammals but no such response has been documented for zebrafish larvae. We hypothesized that differences in exposure routes (inhalation or injection in mammals vs. waterborne in fish) may be a reason for differences in behavioral responses. We characterized cocaine toxicokinetics by liquid chromatography-mass spectrometry (LC-MS/MS) and found its rapid uptake into larvae. We used Matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) imaging for the first time to characterize internal distribution of cocaine in zebrafish larvae. Surprisingly, eyes accumulated the highest amount of cocaine and retained most of it even after 48 h depuration. We attribute this to trapping by pigment melanin, a thus far little explored mechanism that may also be relevant for other basic drugs. Cocaine also reached the brain but with levels similar to those in trunk indicating simple passive diffusion as means of distribution which was supported by toxicokinetic models. Although brain levels covered those known to cause hyperactivity in mammals, only hypoactivity (decreased locomotion) was recorded in zebrafish larvae. Our results therefore point to cocaine's anaesthetic properties as the dominant mechanism of interaction in the fish: upon entry through the fish skin and gills, it first acts on peripheral nerves rapidly overriding any potential stimulatory response in the brain.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping