title: Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis.
abstract: 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.
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany. Christian.Mueller@uk-erlangen.de.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Liubov S
authors.initials: LS
authors.lastname: Kalinichenko
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Tiesel
authors.affiliation: Bruker Daltonik GmbH, Bremen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Witt
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stöckl
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Sprenger
authors.affiliation: Bruker Daltonik GmbH, Bremen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Fuchser
authors.affiliation: Bruker Daltonik GmbH, Bremen, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Beckmann
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Praetner
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Sabine E
authors.initials: SE
authors.lastname: Huber
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Davide
authors.initials: D
authors.lastname: Amato
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Mühle
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Büttner
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Chair of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Irena
authors.initials: I
authors.lastname: Smaga
authors.affiliation: Chair of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Lucyna
authors.initials: L
authors.lastname: Pomierny-Chamiolo
authors.affiliation: Chair of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Pomierny
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Drug Addiction Pharmacology, 12 Smetna, Krakow, 31-343, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Filip
authors.affiliation: Institute of Biochemistry, Friedrich-Alexander-University of Erlangen-Nuremberg, 91054, Erlangen, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Eulenburg
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.|Department of Surgery, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0558, USA.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.affiliation: Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK.
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Lourdusamy
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.|Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 12, 91054, Erlangen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Reichel
authors.affiliation: Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D002755:Choice Behavior / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D003863:Depression / Q000188:drug therapy* / Q000235:genetics; D000431:Ethanol / Q000097:blood / Q000627:therapeutic use*; D005518:Food Preferences / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057897:Reflex, Righting / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D013107:Sphingolipids; D000431:Ethanol; D013482:Superoxide Dismutase; C577975:ASMase, mouse; D013108:Sphingomyelin Phosphodiesterase
keywords: Acid sphingomyelinase; Alcohol; Depression; Drug instrumentalization; Nucleus accumbens; Sphingomyelin