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

Christian P Müller,Thomas Stöckl,Christian Büttner,Christiane Mühle,Irena Smaga,Bartosz Pomierny,Martin Reichel,Davide Amato,Janine Beckmann,Jens Fuchser,Marc Praetner,Matthias Witt,Eva Sprenger,Arif B Ekici,Małgorzata Filip ,Lucyna Pomierny-Chamioło ,Anbarasu Lourdusamy,Sabine Huber ,Erich Gulbins,Volker Eulenburg,L S Kalinichenko ,Jens Tiesel,Johannes Kornhuber

doi:10.1007/s00401-016-1658-6

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.

Highlights

Alcohol is a major psychoactive drug in western societies [24]
A gene expression analysis suggested strong control of Acid sphingomyelinase (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
We show the first mechanism, to our knowledge, of effective alcohol instrumentalization, which is based on ASM action in the brain and an alcohol-induced re-establishment of sphingolipid homeostasis

Summary

Introduction

The majority of adults regularly consume alcohol with the risk of developing an alcohol use disorder (AUD) [13, 63], accompanied by severe brain pathologies [68]. It was shown that alcohol can be instrumentalized, i.e., used to achieve goals that would be impossible to achieve or that require a greater workload without alcohol use [47, 48]. Alcohol use can serve numerous instrumentalization goals, such as the facilitation of social interaction, mating behavior, or stress coping. One of the most important goals is the self-medication for innate or induced psychiatric problems, such as for depression and/or anxiety disorders [5, 47, 54]. While the neuropharmacology of alcohol is well known [17, 73], the neurobiological mechanisms for the potential antidepressant effects of alcohol and their instrumentalization remain poorly understood [34]

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Results

Conclusion