title: From the Cover: Zebrafish Larvae Are Insensitive to Stimulation by Cocaine: Importance of Exposure Route and Toxicokinetics.
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, eg, 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 and found its rapid uptake into larvae. We used Matrix-assisted laser desorption ionization-mass spectrometry 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 anesthetic 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.
authors: *Department of Forensic Pharmacology and Toxicology, University of Zurich, Zurich Institute of Forensic Medicine, Zurich, 8057, Switzerland.|Department of Environmental Toxicology, Eawag, Swiss Federal Institute of Aquatic Science and Technology, Duebendorf, 8600, Switzerland.
authors: Krishna Tulasi
authors: KT
authors: Kirla
authors: Department of Environmental Toxicology, Eawag, Swiss Federal Institute of Aquatic Science and Technology, Duebendorf, 8600, Switzerland.
authors: Ksenia J
authors: KJ
authors: Groh
authors: *Department of Forensic Pharmacology and Toxicology, University of Zurich, Zurich Institute of Forensic Medicine, Zurich, 8057, Switzerland.
authors: Andrea E
authors: AE
authors: Steuer
authors: *Department of Forensic Pharmacology and Toxicology, University of Zurich, Zurich Institute of Forensic Medicine, Zurich, 8057, Switzerland.
authors: Michael
authors: M
authors: Poetzsch
authors: Department of Psychiatry and Neurochemistry, University of Gothenburg, The Sahlgrenska Academy, Institute of Neuroscience and Physiology, Gothenburg, S-41345, Sweden.
authors: Rakesh Kumar
authors: RK
authors: Banote
authors: Department of Environmental Toxicology, Eawag, Swiss Federal Institute of Aquatic Science and Technology, Duebendorf, 8600, Switzerland.|EPFL, School of Architecture, Civil and Environmental Engineering, Lausanne, 1015, Switzerland.
authors: Julita
authors: J
authors: Stadnicka-Michalak
authors: Department of Environmental Toxicology, Eawag, Swiss Federal Institute of Aquatic Science and Technology, Duebendorf, 8600, Switzerland.|ETHZ, Institute of Biogeochemistry and Pollutant Dynamics, Zurich, 8092, Switzerland.
authors: Rik I L
authors: RI
authors: Eggen
authors: Department of Environmental Toxicology, Eawag, Swiss Federal Institute of Aquatic Science and Technology, Duebendorf, 8600, Switzerland kristin.schirmer@eawag.ch.|EPFL, School of Architecture, Civil and Environmental Engineering, Lausanne, 1015, Switzerland.|ETHZ, Institute of Biogeochemistry and Pollutant Dynamics, Zurich, 8092, Switzerland.
authors: Kristin
authors: K
authors: Schirmer
authors: *Department of Forensic Pharmacology and Toxicology, University of Zurich, Zurich Institute of Forensic Medicine, Zurich, 8057, Switzerland.
authors: Thomas
authors: T
authors: Kraemer
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004625:Embryo, Nonmammalian / Q000187:drug effects*; D005880:Gills; D007814:Larva / Q000187:drug effects*; D012867:Skin; D066007:Toxicokinetics; D015027:Zebrafish
chemical_list: D003042:Cocaine
keywords: LC-MS/MS and MALDI imaging; cocaine; distribution; locomotor activity; zebrafish