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Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis
Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325869/ https://www.ncbi.nlm.nih.gov/pubmed/28000031 http://dx.doi.org/10.1007/s00401-016-1658-6 |
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author | Müller, Christian P. Kalinichenko, Liubov S. Tiesel, Jens Witt, Matthias Stöckl, Thomas Sprenger, Eva Fuchser, Jens Beckmann, Janine Praetner, Marc Huber, Sabine E. Amato, Davide Mühle, Christiane Büttner, Christian Ekici, Arif B. Smaga, Irena Pomierny-Chamiolo, Lucyna Pomierny, Bartosz Filip, Malgorzata Eulenburg, Volker Gulbins, Erich Lourdusamy, Anbarasu Reichel, Martin Kornhuber, Johannes |
author_facet | Müller, Christian P. Kalinichenko, Liubov S. Tiesel, Jens Witt, Matthias Stöckl, Thomas Sprenger, Eva Fuchser, Jens Beckmann, Janine Praetner, Marc Huber, Sabine E. Amato, Davide Mühle, Christiane Büttner, Christian Ekici, Arif B. Smaga, Irena Pomierny-Chamiolo, Lucyna Pomierny, Bartosz Filip, Malgorzata Eulenburg, Volker Gulbins, Erich Lourdusamy, Anbarasu Reichel, Martin Kornhuber, Johannes |
author_sort | Müller, Christian P. |
collection | PubMed |
description | Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the establishment of the conditioned behavioral effects of alcohol, and thus drug memories. Opposite effects on drinking and alcohol reward learning were observed in animals with reduced ASM function. Importantly, free-choice alcohol drinking—but not forced alcohol exposure—reduces depression-like behavior selectively in depressed animals through the normalization of brain ASM activity. No such effects were observed in normal mice. ASM hyperactivity caused sphingolipid and subsequent monoamine transmitter hypo-activity in the brain. Free-choice alcohol drinking restores nucleus accumbens sphingolipid- and monoamine homeostasis selectively in depressed mice. A gene expression analysis suggested strong control of ASM on the expression of genes related to the regulation of pH, ion transmembrane transport, behavioral fear response, neuroprotection and neuropeptide signaling pathways. These findings suggest that the paradoxical antidepressant effects of alcohol in depressed organisms are mediated by ASM and its control of sphingolipid homeostasis. Both emerge as a new treatment target specifically for depression-induced alcoholism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-016-1658-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5325869 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-53258692017-03-09 Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis Müller, Christian P. Kalinichenko, Liubov S. Tiesel, Jens Witt, Matthias Stöckl, Thomas Sprenger, Eva Fuchser, Jens Beckmann, Janine Praetner, Marc Huber, Sabine E. Amato, Davide Mühle, Christiane Büttner, Christian Ekici, Arif B. Smaga, Irena Pomierny-Chamiolo, Lucyna Pomierny, Bartosz Filip, Malgorzata Eulenburg, Volker Gulbins, Erich Lourdusamy, Anbarasu Reichel, Martin Kornhuber, Johannes Acta Neuropathol Original Paper Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the establishment of the conditioned behavioral effects of alcohol, and thus drug memories. Opposite effects on drinking and alcohol reward learning were observed in animals with reduced ASM function. Importantly, free-choice alcohol drinking—but not forced alcohol exposure—reduces depression-like behavior selectively in depressed animals through the normalization of brain ASM activity. No such effects were observed in normal mice. ASM hyperactivity caused sphingolipid and subsequent monoamine transmitter hypo-activity in the brain. Free-choice alcohol drinking restores nucleus accumbens sphingolipid- and monoamine homeostasis selectively in depressed mice. A gene expression analysis suggested strong control of ASM on the expression of genes related to the regulation of pH, ion transmembrane transport, behavioral fear response, neuroprotection and neuropeptide signaling pathways. These findings suggest that the paradoxical antidepressant effects of alcohol in depressed organisms are mediated by ASM and its control of sphingolipid homeostasis. Both emerge as a new treatment target specifically for depression-induced alcoholism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-016-1658-6) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2016-12-20 2017 /pmc/articles/PMC5325869/ /pubmed/28000031 http://dx.doi.org/10.1007/s00401-016-1658-6 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Paper Müller, Christian P. Kalinichenko, Liubov S. Tiesel, Jens Witt, Matthias Stöckl, Thomas Sprenger, Eva Fuchser, Jens Beckmann, Janine Praetner, Marc Huber, Sabine E. Amato, Davide Mühle, Christiane Büttner, Christian Ekici, Arif B. Smaga, Irena Pomierny-Chamiolo, Lucyna Pomierny, Bartosz Filip, Malgorzata Eulenburg, Volker Gulbins, Erich Lourdusamy, Anbarasu Reichel, Martin Kornhuber, Johannes Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis |
title | Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis |
title_full | Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis |
title_fullStr | Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis |
title_full_unstemmed | Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis |
title_short | Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis |
title_sort | paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325869/ https://www.ncbi.nlm.nih.gov/pubmed/28000031 http://dx.doi.org/10.1007/s00401-016-1658-6 |
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