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Minimal Age-Related Alterations in Behavioral and Hematological Parameters in Trace Amine-Associated Receptor 1 (TAAR1) Knockout Mice

  • I. S. ZhukovEmail author
  • L. G. Kubarskaya
  • I. Y. Tissen
  • A. A. Kozlova
  • S. G. Dagayev
  • V. A. Kashuro
  • O. L. Vlasova
  • E. L. Sinitca
  • I. V. Karpova
  • R. R. Gainetdinov
Original Research
  • 78 Downloads

Abstract

Since the discovery in 2001, the G protein-coupled trace amine-associated receptor 1 (TAAR1) has become an important focus of research targeted on evaluation of its role in the central nervous system (CNS). Meanwhile, impact of TAAR1 in the peripheral organs is less investigated. Expression of TAAR1 was demonstrated in different peripheral tissues: pancreatic β-cells, stomach, intestines, white blood cells (WBC), and thyroid. However, the role of TAAR1 in regulation of hematological parameters has not been investigated yet. In this study, we performed analysis of anxiety-related behaviors, a complete blood count (CBC), erythrocyte fragility, as well as FT3/FT4 thyroid hormones levels in adult and middle-aged TAAR1 knockout mice. Complete blood count analysis was performed on a Siemens Advia 2120i hematology analyzer and included more than 35 measured and calculated parameters. Erythrocyte fragility test evaluated spherocytosis pathologies of red blood cells (RBC). No significant alterations in essentially all these parameters were found in mice without TAAR1. However, comparative aging analysis has revealed a decreased neutrophils level in the middle-aged TAAR1 knockout mouse group. Minimal alterations in these parameters observed in TAAR1 knockout mice suggest that future TAAR1-based therapies should exert little hematological effect and thus will likely have a good safety profile.

Keywords

Trace amines Anxiety Aging Hematology Thyroid TAAR1 Leukocytes Neutrophils 

Notes

Acknowledgements

This study was supported by the Russian Science Foundation Grant No. 19-75-30008. We are grateful to Lundbeck A/G and Lundbeck USA for generously providing TAAR1 knockout mice.

Author Contributions

ZIS, TIY, KLG, and KIV performed the experiments (CBC, EFT, EPM), wrote the manuscript, acquired the data, and created the figures. SEL and KAA performed the experiments (thyroid parameters) and participated in writing the manuscript. DSG, KVA, VOL, and GRR designed the study and revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

The experiments were carried out in full compliance with ethical standards approved by the FELASA and RusLASA organizations of welfare of laboratory animal use and were approved by the Saint Petersburg State University Ethical Committee for Animal Research.

Supplementary material

10571_2019_721_MOESM1_ESM.xlsx (30 kb)
Electronic supplementary material 1 (XLSX 30 kb)
10571_2019_721_MOESM2_ESM.xlsx (29 kb)
Electronic supplementary material 2 (XLSX 29 kb)

References

  1. Babusyte A, Kotthoff M, Fiedler J, Krautwurst D (2013) Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2. J Leukoc Biol 93:387–394.  https://doi.org/10.1189/jlb.0912433 CrossRefPubMedGoogle Scholar
  2. Berry MD, Gainetdinov RR, Hoener MC, Shahid M (2017) Pharmacology of human trace amine-associated receptors: therapeutic opportunities and challenges. Pharmacol Ther 180:161–180.  https://doi.org/10.1016/j.pharmthera.2017.07.002 CrossRefPubMedGoogle Scholar
  3. Boulton AA (1974) Letter: amines and theories in psychiatry. Lancet (Lond, Engl) 2:52–53CrossRefGoogle Scholar
  4. Dewey MJ, Brown JL, Nallaseth FS (1982) Genetic differences in red cell osmotic fragility: analysis in allophenic mice. Blood 59:986–989PubMedGoogle Scholar
  5. Espinoza S, Lignani G, Caffino L et al (2015) TAAR1 modulates cortical glutamate NMDA receptor function. Neuropsychopharmacology.  https://doi.org/10.1038/npp.2015.65 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Gainetdinov RR, Hoener MC, Berry MD (2018) Trace amines and their receptors. Pharmacol Rev 70:549–620.  https://doi.org/10.1124/pr.117.015305 CrossRefPubMedGoogle Scholar
  7. Hattangadi SM, Wong P, Zhang L et al (2011) From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood 118:6258–6268.  https://doi.org/10.1182/blood-2011-07-356006 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Kahn SE, Watkins BF, Bermes EW (1981) An evaluation of a spectrophotometric scanning technique for measurement of plasma hemoglobin. Ann Clin Lab Sci 11:126–131PubMedGoogle Scholar
  9. Nelson DA, Tolbert MD, Singh SJ, Bost KL (2007) Expression of neuronal trace amine-associated receptor (Taar) mRNAs in leukocytes. J Neuroimmunol 192:21–30.  https://doi.org/10.1016/j.jneuroim.2007.08.006 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Panas MW, Xie Z, Panas HN et al (2012) Trace amine associated receptor 1 signaling in activated lymphocytes. J Neuroimmune Pharmacol 7:866–876.  https://doi.org/10.1007/s11481-011-9321-4 CrossRefPubMedGoogle Scholar
  11. Qatato M, Szumska J, Skripnik V et al (2018) Canonical TSH regulation of cathepsin-mediated thyroglobulin processing in the thyroid gland of male mice requires taar1 expression. Front Pharmacol 9:221.  https://doi.org/10.3389/fphar.2018.00221 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Raab S, Wang H, Uhles S et al (2016) Incretin-like effects of small molecule trace amine-associated receptor 1 agonists. Mol Metab 5:47–56.  https://doi.org/10.1016/j.molmet.2015.09.015 CrossRefPubMedGoogle Scholar
  13. Regard JB, Kataoka H, Cano DA et al (2007) Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. J Clin Invest 117:4034–4043.  https://doi.org/10.1172/JCI32994 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Revel FG, Moreau J-L, Gainetdinov RR et al (2011) TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci USA.  https://doi.org/10.1073/pnas.1103029108 CrossRefPubMedGoogle Scholar
  15. Revel FG, Moreau J-L, Gainetdinov RR et al (2012) Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics. Biol Psychiatry 72:934–942.  https://doi.org/10.1016/j.biopsych.2012.05.014 CrossRefPubMedGoogle Scholar
  16. Sukhanov I, Caffino L, Efimova EV et al (2016) Increased context-dependent conditioning to amphetamine in mice lacking TAAR1. Pharmacol Res 103:206–214.  https://doi.org/10.1016/j.phrs.2015.11.002 CrossRefPubMedGoogle Scholar
  17. Sukhanov I, Espinoza S, Yakovlev DS et al (2014) TAAR1-dependent effects of apomorphine in mice. Int J Neuropsychopharmacol 17:1683–1693.  https://doi.org/10.1017/S1461145714000509 CrossRefPubMedGoogle Scholar
  18. Szumska J, Qatato M, Rehders M et al (2015) Trace amine-associated receptor 1 localization at the apical plasma membrane domain of fisher rat thyroid epithelial cells is confined to cilia. Eur Thyroid J 4:30–41.  https://doi.org/10.1159/000434717 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Vettore L, Zanella A, Molaro L et al (1984) A new test for the laboratory diagnosis of spherocytosis. Acta Haematol 72:258–263.  https://doi.org/10.1159/000206398 CrossRefPubMedGoogle Scholar
  20. Wolinsky TD, Swanson CJ, Smith KE et al (2007) The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav 6:628–639.  https://doi.org/10.1111/j.1601-183X.2006.00292.x CrossRefPubMedGoogle Scholar
  21. Zucchi R, Ghelardoni S, Chiellini G (2010) Cardiac effects of thyronamines. Heart Fail Rev 15:171–176.  https://doi.org/10.1007/s10741-008-9120-z CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • I. S. Zhukov
    • 1
    • 3
    Email author
  • L. G. Kubarskaya
    • 2
  • I. Y. Tissen
    • 3
  • A. A. Kozlova
    • 1
  • S. G. Dagayev
    • 2
  • V. A. Kashuro
    • 2
  • O. L. Vlasova
    • 4
  • E. L. Sinitca
    • 3
  • I. V. Karpova
    • 3
  • R. R. Gainetdinov
    • 1
  1. 1.Institute of Translational Biomedicine and Saint Petersburg University HospitalSaint Petersburg State UniversitySaint PetersburgRussia
  2. 2.Institute of Toxicology of Federal Medical-Biological AgencySaint PetersburgRussia
  3. 3.Institute of Experimental MedicineSaint PetersburgRussia
  4. 4.Peter the Great Saint Petersburg Polytechnic UniversitySaint PetersburgRussia

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