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

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

doi:10.1007/s00401-016-1658-6

Cited by 72 publications

(111 citation statements)

References 71 publications

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“…These findings provide the first mechanistic evidence for alcohol instrumentalization with the goal to self-medicate and ameliorate behavioral symptoms of a genetically induced innate depression. From that, sphingolipid homeostasis emerged as a new mechanism to control depression-alcohol addiction comorbidity (Müller et al 2016 ).…”

Section: Ceramidementioning

confidence: 99%

Ceramide and Its Related Neurochemical Networks as Targets for Some Brain Disorder Therapies

Przegaliński

Müller

et al. 2017

Neurotox Res

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Correlational and causal comparative research link ceramide (Cer), the precursor of complex sphingolipids, to some psychiatric (e.g., depression, schizophrenia (SZ), alcohol use disorder, and morphine antinociceptive tolerance) and neurological (e.g., Alzheimer’s disease (AD), Parkinson disease (PD)) disorders. Cer generation can occur through the de novo synthesis pathway, the sphingomyelinase pathways, and the salvage pathway. The discoveries that plasma Cer concentration increase during depressive episodes in patients and that tricyclic and tetracyclic antidepressants functionally inhibit acid sphingomyelinase (ASM), the enzyme that catalyzes the degradation of sphingomyelin to Cer, have initiated a series of studies on the role of the ASM-Cer system in depressive disorder. Disturbances in the metabolism of Cer or SM are associated with the occurrence of SZ and PD. In both PD and SZ patients, the elevated levels of Cer or SM in the brain regions were associated with the disease. AD patients showed also an abnormal metabolism of brain Cer at early stages of the disease which may suggest Cer as an AD biomarker. In plasma of AD patients and in AD transgenic mice, ASM activity was increased. In contrast, partial ASM inhibition of Aβ deposition improved memory deficits. Furthermore, in clinical and preclinical research, ethanol enhanced activation of ASM followed by Cer production. Limited data have shown that Cer plays an important role in the development of morphine antinociceptive tolerance. In summary, clinical and preclinical findings provide evidence that targeting the Cer system should be considered as an innovative translational strategy for some brain disorders.

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Section: Ceramidementioning

confidence: 99%

Ceramide and Its Related Neurochemical Networks as Targets for Some Brain Disorder Therapies

Przegaliński

Müller

et al. 2017

Neurotox Res

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“…chronic self-administration can induce allostasis in various functional systems of the brain and body periphery(Huber et al, 2017; Becker et al, 2011).…”

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confidence: 99%

Non-pharmacological factors that determine drug use and addiction

Ahmed

Badiani

Miczek

et al. 2020

Neuroscience & Biobehavioral Reviews

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Based on their pharmacological properties, psychoactive drugs are supposed to take control of the natural reward system to finally drive compulsory drug seeking and consumption. However, psychoactive drugs are not used in an arbitrary way as pure pharmacological reinforcement would suggest, but rather in a highly specific manner depending on non-pharmacological factors. While pharmacological effects of psychoactive drugs are well studied, neurobiological mechanisms of non-pharmacological factors are less well understood. Here we review the emerging neurobiological mechanisms beyond pharmacological reinforcement which determine drug effects and use frequency. Important progress was made on the understanding of how the character of an environment and social stress determine drug self-administration. This is expanded by new evidence on how behavioral alternatives and opportunities for drug instrumentalization generate different patterns of drug choice. Emerging evidence suggests that the neurobiology of non-pharmacological factors strongly determines pharmacological and behavioral drug action and may, thus, give rise for an expanded system's approach of psychoactive drug use and addiction.

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“…SMPD4 is also highly expressed in the brain and is important in maintaining sphingolipid metabolism in neuronal system. Sphingolipid homeostasis has been associated with the effects of alcohol on depression [22]. ASE analysis examines the transcriptional differences between two alleles and is designed to identify genes whose expression levels are influenced by the cis-acting elements.…”

Section: Discussionmentioning

confidence: 99%

Allele-Specific Expression and High-Throughput Reporter Assay Reveal Functional Variants in Human Brains with Alcohol Use Disorders

Rao

et al. 2019

Preprint

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Transcriptome studies can identify genes whose expression differs between alcoholics and controls. To test which variants associated with alcohol use disorder (AUDs) may cause expression differences, we integrated deep RNA-seq and genome-wide association studies (GWAS) data from four postmortem brain regions of 30 AUDs subjects and 30 controls (social/non-drinkers) and analyzed allele-specific expression (ASE). We identified 90 genes with differential ASE in subjects with AUDs compared to controls. Of these, 61 genes contained 437 single nucleotide polymorphisms (SNPs) in the 3' untranslated regions (3'UTR) with at least one heterozygote among the subjects studied. Using a modified PASSPORT-seq (parallel assessment of polymorphisms in miRNA target-sites by sequencing) assay, we identified 25SNPs that showed affected RNA levels in a consistent manner in two neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2). Many of these are in binding sites of miRNAs and RNA binding proteins, indicating that these SNPs are likely causal variants of AUD-associated differential ASE.

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

Cited by 72 publications

References 71 publications

Ceramide and Its Related Neurochemical Networks as Targets for Some Brain Disorder Therapies

Ceramide and Its Related Neurochemical Networks as Targets for Some Brain Disorder Therapies

Non-pharmacological factors that determine drug use and addiction

Allele-Specific Expression and High-Throughput Reporter Assay Reveal Functional Variants in Human Brains with Alcohol Use Disorders

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