Send to

Choose Destination
Acta Neuropathol. 2017 Mar;133(3):463-483. doi: 10.1007/s00401-016-1658-6. Epub 2016 Dec 20.

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

Author information

Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
Bruker Daltonik GmbH, Bremen, Germany.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Chair of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.
Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Drug Addiction Pharmacology, 12 Smetna, Krakow, 31-343, Poland.
Institute of Biochemistry, Friedrich-Alexander-University of Erlangen-Nuremberg, 91054, Erlangen, Germany.
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.
Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK.
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 12, 91054, Erlangen, Germany.


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.


Acid sphingomyelinase; Alcohol; Depression; Drug instrumentalization; Nucleus accumbens; Sphingomyelin

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center