Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis

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Details zur Publikation

Autor(en): Müller C, Kalinichenko L, Tiesel J, Witt M, Stöckl T, Sprenger E, Fuchser J, Beckmann J, Praetner M, Huber S, Amato D, Mühle C, Büttner C, Ekici AB, Smaga I, Pomierny-Chamiolo L, Pomierny B, Filip M, Eulenburg V, Gulbins E, Lourdusamy A, Reichel M, Kornhuber J
Zeitschrift: Acta Neuropathologica
Jahr der Veröffentlichung: 2016
ISSN: 0001-6322


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.

FAU-Autoren / FAU-Herausgeber

Amato, Davide PD Dr.
Psychiatrische und Psychotherapeutische Klinik
Büttner, Christian
Lehrstuhl für Humangenetik
Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
Eulenburg, Volker PD Dr.
Lehrstuhl für Biochemie und Molekulare Medizin
Huber, Sabine
Professur für Suchtmedizin
Kalinichenko, Liubov
Professur für Suchtmedizin
Kornhuber, Johannes Prof. Dr. med.
Lehrstuhl für Psychiatrie und Psychotherapie
Mühle, Christiane Dr. rer. nat.
Psychiatrische und Psychotherapeutische Klinik
Müller, Christiane
Medizinische Fakultät
Reichel, Martin PD Dr.
Psychiatrische und Psychotherapeutische Klinik
Stöckl, Thomas Dr. med.
Psychiatrische und Psychotherapeutische Klinik
Tiesel, Jens
Professur für Suchtmedizin

Autor(en) der externen Einrichtung(en)
Bruker Daltonik GmbH
Jagiellonian University / Uniwersytet Jagielloński (UJ)
Polska Akademia Nauk (PAN) / Polish Academy of Sciences
Universität Duisburg-Essen (UDE)
University of Nottingham


Müller, C., Kalinichenko, L., Tiesel, J., Witt, M., Stöckl, T., Sprenger, E.,... Kornhuber, J. (2016). Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis. Acta Neuropathologica.

Müller, Christiane, et al. "Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis." Acta Neuropathologica (2016).


Zuletzt aktualisiert 2018-10-10 um 08:19