Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
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
_version_ 1782510440068153344
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
work_keys_str_mv AT mullerchristianp paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT kalinichenkoliubovs paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT tieseljens paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT wittmatthias paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT stocklthomas paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT sprengereva paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT fuchserjens paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT beckmannjanine paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT praetnermarc paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT hubersabinee paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT amatodavide paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT muhlechristiane paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT buttnerchristian paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT ekiciarifb paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT smagairena paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT pomiernychamiololucyna paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT pomiernybartosz paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT filipmalgorzata paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT eulenburgvolker paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT gulbinserich paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT lourdusamyanbarasu paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT reichelmartin paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis
AT kornhuberjohannes paradoxicalantidepressanteffectsofalcoholarerelatedtoacidsphingomyelinaseanditscontrolofsphingolipidhomeostasis