The Effects of Chronic Amitriptyline on Zebrafish Behavior and Monoamine Neurochemistry
Amitriptyline is a commonly used tricyclic antidepressant (TCA) inhibiting serotonin and norepinephrine reuptake. The exact CNS action of TCAs remains poorly understood, necessitating new screening approaches and novel model organisms. Zebrafish (Danio rerio) are rapidly emerging as a promising tool for pharmacological research of antidepressants, including amitriptyline. Here, we examine the effects of chronic 2-week exposure to 10 and 50 μg/L amitriptyline on zebrafish behavior and monoamine neurotransmitters. Overall, the drug at 50 μg/L evoked pronounced anxiolytic-like effects in the novel tank test (assessed by more time in top, fewer transition and shorter latency to enter the top). Like other TCAs, amitriptyline reduced serotonin turnover, but also significantly elevated whole-brain norepinephrine and dopamine levels. The latter effect was not reported in this model previously, and accompanied higher brain expression of tyrosine hydroxylase (a rate-limiting enzyme of catecholamine biosynthesis), but unaltered expression of dopamine-β-hydroxylase and monoamine oxidase (the enzymes of dopamine metabolism). This response may underlie chronic amitriptyline action on dopamine and norepinephrine neurotransmission, and contribute to the complex CNS profile of this drug observed both clinically and in animal models. Collectively, these findings also confirm the important role of monoamine modulation in the regulation of anxiety-related behavior in zebrafish, and support the utility of this organism as a promising in-vivo model for CNS drug screening.
KeywordsZebrafish Amitriptyline Tricyclic antidepressants Serotonin Dopamine Norephnephrine
Laboratory zebrafish maintenance for this project was performed by the Environmental Safety Observatory Bioelectronic Complex of SPSU. The research was supported by the Russian Foundation for Basic Research (RFBR) grants 16-04-00851 to АVK, and 18-315-00375 to DAM. RRG was supported by a Russian Science Foundation (RSF) grant 14-50-00069.
- 2.Baker DR, Kasprzyk-Hordern B (2011) Multi-residue determination of the sorption of illicit drugs and pharmaceuticals to wastewater suspended particulate matter using pressurised liquid extraction, solid phase extraction and liquid chromatography coupled with tandem mass spectrometry. J Chromatogr A 1218:7901–7913CrossRefPubMedGoogle Scholar
- 3.Brady LS, Whitfield HJ Jr, Fox RJ, Gold PW, Herkenham M (1991) Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. J Clin Invest 87:831–837CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Guaiana G, Barbui C, Hotopf M (2007) Amitriptyline for depression. Cochrane Database Syst Rev CD004186Google Scholar
- 18.Kalueff AV, Gebhardt M, Stewart AM, Cachat JM, Brimmer M, Chawla JS, Craddock C, Kyzar EJ, Roth A, Landsman S, Gaikwad S, Robinson K, Baatrup E, Tierney K, Shamchuk A, Norton W, Miller N, Nicolson T, Braubach O, Gilman CP, Pittman J, Rosemberg DB, Gerlai R, Echevarria D, Lamb E, Neuhauss SC, Weng W, Bally-Cuif L, Schneider H, Zebrafish Neuroscience Research C (2013) Towards a comprehensive catalog of zebrafish behavior 1.0 and beyond. Zebrafish 10:70–86CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Kasprzyk-Hordern B, Dinsdale RM, Guwy AJ (2008) Multiresidue methods for the analysis of pharmaceuticals, personal care products and illicit drugs in surface water and wastewater by solid-phase extraction and ultra performance liquid chromatography-electrospray tandem mass spectrometry. Anal Bioanal Chem 391:1293–1308CrossRefPubMedGoogle Scholar
- 23.Khan KM, Collier AD, Meshalkina DA, Kysil EV, Khatsko SL, Kolesnikova T, Morzherin YY, Warnick JE, Kalueff AV, Echevarria DJ (2017) Zebrafish models in neuropsychopharmacology and CNS drug discovery. Br J Pharmacol 173:1925–1944Google Scholar
- 26.Kroner JW, Peugh J, Kashikar-Zuck SM, LeCates SL, Allen JR, Slater SK, Zafar M, Kabbouche MA, O’Brien HL, Shenk CE, Kroon Van Diest AM, Hershey AD, Powers SW (2017) Trajectory of Improvement in children and adolescents with chronic migraine: results from the cognitive-behavioral therapy and amitriptyline trial. J Pain 18:637–644CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Leucht C, Huhn M, Leucht S (2012) Amitriptyline versus placebo for major depressive disorder. Cochrane Database Syst Rev 12: CD009138Google Scholar
- 43.Sackerman J, Donegan JJ, Cunningham CS, Nguyen NN, Lawless K, Long A, Benno RH, Gould GG (2010) Zebrafish Behavior in Novel Environments: Effects of Acute Exposure to Anxiolytic Compounds and Choice of Danio rerio Line. Int J Comp 23:43–61Google Scholar
- 51.Westerfield M (2000) The zebrafish book: a guide for the laboratory use of zebrafish (Danio rerio). University of Oregon Press, EugeneGoogle Scholar