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Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT(2C) receptor in the mouse brain

BACKGROUND: Serotonin (5-HT) 5-HT(2C) receptor mRNA editing (at five sites, A–E), implicated in neuropsychiatric disorders, including clinical depression, remains unexplored during alcohol abstinence—often accompanied by depressive symptoms. METHODS: We used deep sequencing to investigate 5-HT(2C) r...

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Autores principales: Zaniewska, Magdalena, Alenina, Natalia, Fröhler, Sebastian, Chen, Wei, Bader, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661786/
https://www.ncbi.nlm.nih.gov/pubmed/37923824
http://dx.doi.org/10.1007/s43440-023-00545-6
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author Zaniewska, Magdalena
Alenina, Natalia
Fröhler, Sebastian
Chen, Wei
Bader, Michael
author_facet Zaniewska, Magdalena
Alenina, Natalia
Fröhler, Sebastian
Chen, Wei
Bader, Michael
author_sort Zaniewska, Magdalena
collection PubMed
description BACKGROUND: Serotonin (5-HT) 5-HT(2C) receptor mRNA editing (at five sites, A–E), implicated in neuropsychiatric disorders, including clinical depression, remains unexplored during alcohol abstinence—often accompanied by depressive symptoms. METHODS: We used deep sequencing to investigate 5-HT(2C) receptor editing in mice during early ethanol deprivation following prolonged alcohol exposure and mice lacking tryptophan hydroxylase (TPH)2, a key enzyme in central 5-HT production. We also examined Tph2 expression in ethanol-deprived animals using quantitative real-time PCR (qPCR). RESULTS: Cessation from chronic 10% ethanol exposure in a two-bottle choice paradigm enhanced immobility time and decreased latency in the forced swim test (FST), indicating a depression-like phenotype. In the hippocampus, ethanol-deprived “high ethanol-drinking” mice displayed reduced Tph2 expression, elevated 5-HT(2C) receptor editing efficiency, and decreased frequency of the D mRNA variant, encoding the less-edited INV protein isoform. Tph2(–/–) mice showed attenuated receptor editing in the hippocampus and elevated frequency of non-edited None and D variants. In the prefrontal cortex, Tph2 deficiency increased receptor mRNA editing at site D and reduced the frequency of AB transcript, predicting a reduction in the corresponding partially edited VNI isoform. CONCLUSIONS: Our findings reveal differential effects of 5-HT depletion and ethanol cessation on 5-HT(2C) receptor editing. Central 5-HT depletion attenuated editing in the prefrontal cortex and the hippocampus, whereas ethanol deprivation, coinciding with reduced Tph2 expression in the hippocampus, enhanced receptor editing efficiency specifically in this brain region. This study highlights the interplay between 5-HT synthesis, ethanol cessation, and 5-HT(2C) receptor editing, providing potential mechanism underlying increased ethanol consumption and deprivation. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-023-00545-6.
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spelling pubmed-106617862023-11-03 Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT(2C) receptor in the mouse brain Zaniewska, Magdalena Alenina, Natalia Fröhler, Sebastian Chen, Wei Bader, Michael Pharmacol Rep Article BACKGROUND: Serotonin (5-HT) 5-HT(2C) receptor mRNA editing (at five sites, A–E), implicated in neuropsychiatric disorders, including clinical depression, remains unexplored during alcohol abstinence—often accompanied by depressive symptoms. METHODS: We used deep sequencing to investigate 5-HT(2C) receptor editing in mice during early ethanol deprivation following prolonged alcohol exposure and mice lacking tryptophan hydroxylase (TPH)2, a key enzyme in central 5-HT production. We also examined Tph2 expression in ethanol-deprived animals using quantitative real-time PCR (qPCR). RESULTS: Cessation from chronic 10% ethanol exposure in a two-bottle choice paradigm enhanced immobility time and decreased latency in the forced swim test (FST), indicating a depression-like phenotype. In the hippocampus, ethanol-deprived “high ethanol-drinking” mice displayed reduced Tph2 expression, elevated 5-HT(2C) receptor editing efficiency, and decreased frequency of the D mRNA variant, encoding the less-edited INV protein isoform. Tph2(–/–) mice showed attenuated receptor editing in the hippocampus and elevated frequency of non-edited None and D variants. In the prefrontal cortex, Tph2 deficiency increased receptor mRNA editing at site D and reduced the frequency of AB transcript, predicting a reduction in the corresponding partially edited VNI isoform. CONCLUSIONS: Our findings reveal differential effects of 5-HT depletion and ethanol cessation on 5-HT(2C) receptor editing. Central 5-HT depletion attenuated editing in the prefrontal cortex and the hippocampus, whereas ethanol deprivation, coinciding with reduced Tph2 expression in the hippocampus, enhanced receptor editing efficiency specifically in this brain region. This study highlights the interplay between 5-HT synthesis, ethanol cessation, and 5-HT(2C) receptor editing, providing potential mechanism underlying increased ethanol consumption and deprivation. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-023-00545-6. Springer International Publishing 2023-11-03 2023 /pmc/articles/PMC10661786/ /pubmed/37923824 http://dx.doi.org/10.1007/s43440-023-00545-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zaniewska, Magdalena
Alenina, Natalia
Fröhler, Sebastian
Chen, Wei
Bader, Michael
Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT(2C) receptor in the mouse brain
title Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT(2C) receptor in the mouse brain
title_full Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT(2C) receptor in the mouse brain
title_fullStr Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT(2C) receptor in the mouse brain
title_full_unstemmed Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT(2C) receptor in the mouse brain
title_short Ethanol deprivation and central 5-HT deficiency differentially affect the mRNA editing of the 5-HT(2C) receptor in the mouse brain
title_sort ethanol deprivation and central 5-ht deficiency differentially affect the mrna editing of the 5-ht(2c) receptor in the mouse brain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661786/
https://www.ncbi.nlm.nih.gov/pubmed/37923824
http://dx.doi.org/10.1007/s43440-023-00545-6
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