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: Christian P Müller, Liubov S Kalinichenko, Jens Tiesel, Matthias Witt, Thomas Stöckl, Eva Sprenger, Jens Fuchser, Janine Beckmann, Marc Praetner, Sabine E Huber, Davide Amato, Christiane Mühle, Christian Büttner, Arif B Ekici, Irena Smaga, Lucyna Pomierny-Chamiolo, Bartosz Pomierny, Malgorzata Filip, Volker Eulenburg, Erich Gulbins, Anbarasu Lourdusamy, Martin Reichel, Johannes Kornhuber
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 133 Issue 3 Pg. 463-483 (03 2017) ISSN: 1432-0533 [Electronic] Germany
• PMID: 28000031 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antidepressive Agents
• Sphingolipids
• Ethanol
• Superoxide Dismutase
• ASMase, mouse
• Sphingomyelin Phosphodiesterase

Topics

• Animals
• Antidepressive Agents (therapeutic use)
• Choice Behavior (drug effects)
• Conditioning, Operant (drug effects)
• Depression (drug therapy, genetics)
• Ethanol (blood, therapeutic use)
• Food Preferences (drug effects)
• Gene Expression Regulation (drug effects, genetics)
• Homeostasis (genetics)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Reflex, Righting (drug effects, genetics)
• Signal Transduction (drug effects, genetics)
• Sphingolipids (metabolism)
• Sphingomyelin Phosphodiesterase (genetics, metabolism)
• Superoxide Dismutase (genetics, metabolism)