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The Role of the AgRP 25-51 Active Fragment in the Regulation of Functional Activity of Locus Coeruleus Norepinephrinergic Neurons and in Norepinephrine Biosynthesis

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Abstract

Double fluorescence immunolabeling and confocal microscopy showed that the nerve processes immediately surrounding norepinephrinergic (NE) neurons in the brainstem locus coeruleus (LC) are immunopositive to AgRP (agouti gene-related protein), and that NE neurons express melanocortin receptor type 3, but not 4, on their bodies. These findings suggest that the active AgRP 83–132 fragment is able to directly affect NE neurons. In C57BL/6J mice, 3 h after the injection of the AgRP 25–51 fragment (whose action is not mediated by G protein-coupled melanocortin receptors) into the LC, it exhibited an inhibitory effect on NE neurons. The immunolabeling of LC neurons revealed no changes in the level of tyrosine hydroxylase phosphorylated at serine-40, but a significant decrease in levels of tyrosine hydroxylase phosphorylated at serine-31 and dopamine-β-hydroxylase. Real-time PCR showed that after AgRP 25–51 injection, there was a significant decrease in levels of tyrosine hydroxylase mRNA, norepinephrine transporter mRNA, and mRNA of GABA biosynthesis enzymes GAD65/67. HPLC demonstrated that after AgRP 25–51 injection into the LC, the NE level in the striatum and orbitofrontal cortex, i.e. main targets of LC NE neurons, also decreased. The article discusses the mechanisms of interaction of the melanocortin system with LC NE neurons.

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Funding

This work was supported by the State budget (theme reg. no. АААА-А18-118012290427-7).

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Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Scienses, St. Petersburg, Russia

    A. L. Mikhrina, L. O. Saveleva, I. Yu. Morina & I. V. Romanova

Authors
  1. A. L. Mikhrina
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  2. L. O. Saveleva
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  3. I. Yu. Morina
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  4. I. V. Romanova
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Contributions

The basic idea and experimental design (A.L.M., I.V.R.); conducting experiments and data collection (A.L.M., L.O.S.); data processing (A.L.M., L.O.S., I.Yu.M.); writing and editing the manuscript (A.L.M., I.V.R.).

Corresponding author

Correspondence to I. V. Romanova.

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COMPLIANCE WITH ETHICAL STANDARDS

All applicable international, national and institutional principles of handling and using experimental animals for scientific purposes were observed.

This study did not involve human subjects as research objects.

СONFLICT OF INTEREST

The authors declare that they have no conflict of interest that might be associated with the publication of this article.

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Translated by A. Polyanovsky

Russian Text © The Author(s), 2021, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2021, Vol. 107, No. 12, pp. 1542–1552https://doi.org/10.31857/S0869813921120074.

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Mikhrina, A.L., Saveleva, L.O., Morina, I.Y. et al. The Role of the AgRP 25-51 Active Fragment in the Regulation of Functional Activity of Locus Coeruleus Norepinephrinergic Neurons and in Norepinephrine Biosynthesis. J Evol Biochem Phys 57, 1490–1498 (2021). https://doi.org/10.1134/S0022093021060259

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  • DOI: https://doi.org/10.1134/S0022093021060259

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