The effect of zaleplon on metabolic changes in neurotransmitters and toxic effects in Danio fish

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Abstract

Introduction. Z-drugs are a group of “non-benzodiazepine” drugs with the main mode of action regulating sleep behavior in humans through exposure to GABA receptors. There are reports indicating the toxic effects of overdose and abuse of zaleplon. However, information on the effect of Z-drugs on neurotransmitter levels is scarce.

The aim of this study was to study the effect of zaleplon exposure on neurotransmitter levels in the larvae of Danio fish using targeted metabolomics.

Material and methods. 4-hour exposure to zaleplon in concentrations of 0.1, 1.0, 10, 100 and 1000 μg/l was carried out on the larvae of Danio fish. Intervention groups were compared with control groups. Each group consisted of 20 larvae of Danio fish. Neurotransmitters and their metabolites were measured using high-performance liquid chromatography combined with tandem mass spectrometry (HPLC-MS/MS).

Results. Twenty-two metabolites associated with neurotransmission were quantified. Significantly increased metabolites were tryptophan, serotonin, 5-hydroxyindolacetic acid, acetylserotonin, epinephrine and choline. Significantly reduced metabolites were 5-hydroxytryptophan, 5-methoxytryptamine, dopamine, normetanephrine, metanephrine, kynurenine, 3-hydroxykinurenine, anthranilic acid and gamma-aminobutyric acid.

Limitation. When studying metabolic changes in neurotransmitters and toxic effects in Danio fish, the results of a group of 20 larvae were analyzed, which is a sufficient sample to state the results obtained.

Conclusion. Exposure to zaleplon caused metabolic changes in the concentrations of neurotransmitters associated with most major neurotransmitter systems.

Compliance with ethical standards. The study does not require the submission of a biomedical ethics committee opinion or other documents, as the study was conducted on fish embryos in accordance with SIS 33774-2016 “Testing chemicals that pose a danger to the environment. Acute toxicity of fish embryos (FET)”.

Author contribution. All co-authors made an equal contribution to the research and preparation of the article for publication.

Conflict of interests. The authors declare no conflict of interest. 

Funding. The study was not sponsored.

Received: December 27, 2022 / Accepted: May 26, 2023 / Published: June 30, 2023

About the authors

Alla Andreevna Volkova

FGBU “Russian Center of Forensic Medical Examination”; FGAOU VO “Peoples’ Friendship University of Russia”

Author for correspondence.
Email: noemail@neicon.ru

Кандидат фармацевтических наук, научный сотрудник ФГБУ «Российский центр судебно-медицинской экспертизы» МЗ РФ, 125284, Москва, Россия.

e-mail: himija@rc-sme.ru

Russian Federation

Roman Anatolievich Kalekin

FGBU “Russian Center of Forensic Medical Examination”; FGAOU VO “Peoples’ Friendship University of Russia”

Email: noemail@neicon.ru

Доктор фармацевтических наук, научный сотрудник ФГБУ «Российский центр судебно-медицинской экспертизы» МЗ РФ, 125284, Москва, Россия.

e-mail: himija@rc-sme.ru

Russian Federation

Alevtina Mikhailovna Orlova

FGBU “Russian Center of Forensic Medical Examination”

Email: himija@rc-sme.ru

Ph.D. in Pharmaceutical Sciences, Leading Researcher of Russian Center of Forensic Medical Examination, Moscow.

e-mail: himija@rc-sme.ru

Russian Federation

Albina Zakharovna Pavlova

FGBU “Russian Center of Forensic Medical Examination”; FGBNU “Scientific Research Institute of Human Morphology named after Academician A.P. Avtsyn” Ministry of Education and Science of Russia

Email: noemail@neicon.ru

Доктор биологических наук, научный сотрудник ФГБУ «Российский центр судебно-медицинской экспертизы» МЗ РФ, 125284, Москва, Россия.

e-mail: himija@rc-sme.ru

Russian Federation

Olga Genrikhovna Astashkina

FGBU “Russian Center of Forensic Medical Examination”; GBUZ “Bureau of Forensic Medical Examination” of the Moscow Department of Health

Email: noemail@neicon.ru

Доктор медицинских наук, научный сотрудник ФГБУ «Российский центр судебно-медицинской экспертизы» МЗ РФ, 125284, Москва, Россия.

e-mail: himija@rc-sme.ru

Russian Federation

Andrey Leonidovich Pavlov

FGBU “Russian Center of Forensic Medical Examination”; GBU of Moscow Center for Rehabilitation of disabled people “Tsaritsyno”

Email: noemail@neicon.ru

Врач, ГБУ г. Москвы «Центр реабилитации инвалидов «Царицыно»» Департамента труда и социальной защиты населения города Москвы, 117534, Москва, Россия.

e-mail: himija@rc-sme.ru

Russian Federation

References

  1. Brandt J., Leong C. Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research. Drugs in R and D. 2017; 17(4). https://doi.org/10.1007/s40268-017-0207-7
  2. Gunja N. The Clinical and Forensic Toxicology of Z-drugs. Journal of Medical Toxicology. 2013; 9(2). https://doi.org/10.1007/s13181-013-0292-0
  3. Gunja N. In the Zzz Zone: The Effects of Z-Drugs on Human Performance and Driving. Journal of Medical Toxicology. 2013; 9(2). https://doi.org/10.1007/s13181-013-0294-y
  4. Schifano F., Chiappini S., Corkery J.M., Guirguis A. An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions. International Journal of Neuropsychopharmacology. 2019; 22(4). https://doi.org/10.1093/ijnp/pyz007
  5. Volkova A.A., Kalekin R.A., Orlova A.M., Moskaleva N.E., Markin P.A., Astashkina O.G. Chemical and toxicological examination of zaleplon and its metabolites in the biological object urine . Voprosy biologicheskoj, medicinskoj i farmacevticheskoj himii. 2022; 25(4): 15–22. https://doi.org/10.29296/25877313-2022-04-03 (in Russian)
  6. Kalekin R.A., Moskaleva N.E., Volkova A.A., Orlova A.M., Markin P.A., Nevmyatova S.R., Appolonova S.A. Determination of zaleplon and klobazam by high-performance liquid chromatography – tandem mass spectrometry with high resolution using Orbitrap technology. Sudebno-medicinskaya ekspertiza. 2022; 65(2): 24–8. https://doi.org/10.17116/sudmed20226502124 (in Russian)
  7. Markin P.A., Moskaleva N.E., Appolonova S.A., Volkova A.A., Orlova A.M., Kalekin R.A., Nevmyatova S.R. Development of a thin-layer chromatography method for simultaneous determination of klobazam and zaleplon in a mixture. In the collection: Topical issues of forensic medicine and law. Collection of scientific and practical articles. Kazan: 2021; 158–61. (in Russian
  8. Cassar S., Adatto I., Freeman J.L., Gamse J.T., Iturria I., Lawrence C., Muriana A., Peterson R.T., van Cruchten S., Zon L.I. Use of Zebrafish in Drug Discovery Toxicology. Chemical Research in Toxicology. https://doi.org/10.1021/acs.chemrestox.9b00335
  9. Robinson N.B., Krieger K., Khan F., Huffman W., Chang M., Naik A., Yongle R., Hameed I., Krieger K., Girardi L.N., Gaudino M. The current state of animal models in research: a review. International Journal of Surgery. 72: 9–13. https://doi.org/10.1016/j.ijsu.2019.10.015
  10. Kalueff A.v., Stewart A.M., Gerlai R. Zebrafish as an emerging model for studying complex brain disorders. In Trends in Pharmacological Sciences. 2014: 35(2): 63–75. https://doi.org/10.1016/j.tips.2013.12.002
  11. Markin P.A., Brito A., Moskaleva N.E., Tagliaro F., la Frano M.R., Savitskii M.V., Appolonova S.A. Short- and long-term exposures of the synthetic cannabinoid 5F-APINAC induce metabolomic alterations associated with neurotransmitter systems and embryotoxicity confirmed by teratogenicity in zebrafish. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology. 2021; 243: 109000. https://doi.org/10.1016/j.cbpc.2021.109000
  12. Markin Pavel A., Brito A., Moskaleva N.E., Tagliaro F., Tarasov V.v., la Frano M.R., Savitskii M.v., Appolonova S.A. Short- and medium-term exposures of diazepam induce metabolomic alterations associated with the serotonergic, dopaminergic, adrenergic and aspartic acid neurotransmitter systems in zebrafish (Danio rerio) embryos/larvae. Comparative Biochemistry and Physiology Part D: Genomics and Proteomics. 2021; 38: 100816. https://doi.org/10.1016/j.cbd.2021.100816
  13. Haleem D.J., Batool F. Regionally specific effects of diazepam on brain serotonin metabolism in rats: Sustained effects following repeated administration. Life Sciences. 1996; 59(15): PL239–46. https://doi.org/10.1016/0024-3205(96)00452-3
  14. Mets M.A.J., de Vries J.M., de Senerpont Domis L.M., Volkerts E.R., Olivier B., Verster J.C. Next-day effects of ramelteon (8 mg), zopiclone (7.5 mg), and placebo on highway driving performance, memory functioning, psychomotor performance, and mood in healthy adult subjects. Sleep. 2011; 34(10): 1327–34. https://doi.org/10.5665/SLEEP.1272
  15. Boyda H.N., Ho A.A., Tse L., Procyshyn R.M., Yuen J.W.Y., Kim D.D., Honer W.G., Barr A.M. Differential Effects of Acute Treatment With Antipsychotic Drugs on Peripheral Catecholamines. Frontiers in Psychiatry. 2020; 11: 617428. https://doi.org/10.3389/fpsyt.2020.617428
  16. Roy-Byrne P., Fleishaker J., Arnett C., Dubach M., Stewart J., Radant A., Veith R., Graham M. Effects of acute and chronic Alprazolam treatment on cerebral blood flow, memory, sedation, and plasma catecholamines. Neuropsychopharmacology. 1993; 8(2): 161–9. https://doi.org/10.1038/npp.1993.18
  17. Schwarcz R., Stone T.W. The kynurenine pathway and the brain: Challenges, controversies and promises. Neuropharmacology. 2017; 112: 237–47. https://doi.org/10.1016/j.neuropharm.2016.08.003
  18. Eissa A.A.H.M., Soliman G.A.E.H., Khataibeh M.H. Design, synthesis and anti-inflammatory activity of structurally simple anthranilic acid congeners devoid of ulcerogenic side effects. Chemical and Pharmaceutical Bulletin. 2012; 60(10): 1290–300. https://doi.org/10.1248/cpb.c12-00516
  19. Richter G., Liao V.W.Y., Ahring P.K., Chebib M. The Z-Drugs Zolpidem, Zaleplon, and Eszopiclone Have Varying Actions on Human GABAA Receptors Containing γ1, γ2, and γ3 Subunits. Frontiers in Neuroscience. 2020; 14: 599812. https://doi.org/10.3389/fnins.2020.599812

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Copyright (c) 2023 Volkova A.A., Kalekin R.A., Orlova A.M., Pavlova A.Z., Astashkina O.G., Pavlov A.L.


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