title: Effects of a non-competitive N-methyl-d-aspartate (NMDA) antagonist, tiletamine, in adult zebrafish.
abstract: Tiletamine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist chemically related to ketamine and phencyclidine. A common veterinary anesthetic drug, tiletamine is currently a Schedule III controlled substance in USA. This compound exerts sedative effects in humans and animals, also having an abuse potential, toxicity and dissociative hallucinogenic properties clinically. However, the neurotropic profile of tiletamine remains poorly understood, necessitating novel models and in-vivo screens, including non-mammalian species. Zebrafish (Danio rerio) are rapidly becoming a popular model organism for screening various CNS drugs, including those acting at NMDA receptors. Here, we investigated acute behavioral effects of 1, 5 and 10mg/L of tiletamine on adult zebrafish. In the standard novel tank test, a 20-min immersion in 1mg/L of tiletamine produced no overt differences from control zebrafish (receiving 0.1% DMSO vehicle), except for reduced top entries. In contrast, tiletamine at 5 and 10mg/L exerted robust dose-dependent sedative effects in zebrafish (also darkening their skin coloration, similar to ketamine and PCP). Gas chromatography/mass spectrometry (GC/MS) analyses revealed no tiletamine peaks in control and 1mg/L groups, but detected tiletamine peaks in zebrafish brain samples at 5 and 10mg/L. Together, these findings demonstrate potent neurotropic effects of tiletamine in zebrafish, and their high sensitivity to this drug. Our findings also support the growing utility of fish-based aquatic screens for studying neuroactive properties of NMDA antagonists in-vivo.
authors.affiliation: Ural Federal University, Ekaterinburg 620002, Russia.
authors.forename: Tatiana O
authors.initials: TO
authors.lastname: Kolesnikova
authors.affiliation: Ural Federal University, Ekaterinburg 620002, Russia.
authors.forename: Sergey L
authors.initials: SL
authors.lastname: Khatsko
authors.affiliation: Ural Federal University, Ekaterinburg 620002, Russia; Management of Federal Drug Control Service of Russia in Sverdlovsk Region, 31 Razin Str., Ekaterinburg 620142, Russia.
authors.forename: Vadim A
authors.initials: VA
authors.lastname: Shevyrin
authors.affiliation: Ural Federal University, Ekaterinburg 620002, Russia. Electronic address: yu.yu.morzherin@urfu.ru.
authors.forename: Yuri Yu
authors.initials: YY
authors.lastname: Morzherin
authors.affiliation: Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg 199034, Russia. Electronic address: avkalueff@gmail.com.
authors.forename: Allan V
authors.initials: AV
authors.lastname: Kalueff
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013992:Tiletamine / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: D006993:Hypnotics and Sedatives; D016194:Receptors, N-Methyl-D-Aspartate; D013992:Tiletamine
keywords: Aquatic screening; Central glutamatergic system; Ketamine; Sedative effects; Tiletamine; Zebrafish