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The Effects of Chronic Amitriptyline on Zebrafish Behavior and Monoamine Neurochemistry

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Abstract

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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Institute of Translational Biomedicine, St. Petersburg University, St. Petersburg, Russia

    Darya A. Meshalkina, Elana V. Kysil, Kristina A. Antonova, Konstantin A. Demin & Raul R. Gainetdinov

  2. Ural Federal University, Ekaterinburg, Russia

    Tatiana O. Kolesnikova & Sergey L. Khatsko

  3. Skolkovo Institute of Science and Technology, Skoltech, Moscow, Russia

    Raul R. Gainetdinov

  4. Institute of Experimental Medicine, Almazov National Medical Research Centre, St. Petersburg, Russia

    Konstantin A. Demin & Polina A. Alekseeva

  5. School of Pharmaceutical Sciences, Southwest University, Chongqing, China

    Allan V. Kalueff

  6. Laboratory of Biological Psychiatry, Institute of Translational Biomedicine, St. Petersburg University, St. Petersburg, Russia

    Allan V. Kalueff

  7. Laboratory of Petrochemistry, Ural Federal University, Ekaterinburg, Russia

    Allan V. Kalueff

  8. Almazov National Medical Research Centre, St. Petersburg, Russia

    Allan V. Kalueff

  9. Granov Russian National Research Center for Radiology and Surgical Technologies, Pesochny, Russia

    Allan V. Kalueff

  10. ZENEREI Research Center, Slidell, LA, USA

    Allan V. Kalueff

  11. The International Zebrafish Neuroscience Research Consortium (ZNRC), Slidell, LA, USA

    Allan V. Kalueff

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  1. Darya A. Meshalkina
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  2. Elana V. Kysil
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  3. Kristina A. Antonova
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  4. Konstantin A. Demin
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  5. Tatiana O. Kolesnikova
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  8. Polina A. Alekseeva
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  9. Allan V. Kalueff
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Correspondence to Allan V. Kalueff.

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Meshalkina, D.A., Kysil, E.V., Antonova, K.A. et al. The Effects of Chronic Amitriptyline on Zebrafish Behavior and Monoamine Neurochemistry. Neurochem Res 43, 1191–1199 (2018). https://doi.org/10.1007/s11064-018-2536-5

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  • DOI: https://doi.org/10.1007/s11064-018-2536-5

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