Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males

Kalinichenko LS 1 , Mühle C 1 , Jia T 2 , Anderheiden F 1 , Datz M 1 , Eberle AL 1 Show all authors , Eulenburg V 3 , Granzow J 1 , Hofer M 1 , Hohenschild J 1 , Huber SE 1 , Kämpf S 1 , Kogias G 1 , Lacatusu L 1 , Lugmair C 1 , Taku SM 1 , Meixner D 1 , Sembritzki NK 1 , Praetner M 1 , Rhein C 1 , Sauer C 1 , Scholz J 1 , Ulrich F 1 , Valenta F 1 , Weigand E 1 , Werner M 1 , Tay N 2 , Mc Veigh CJ 4 , Haase J 4 , Wang AL 5 , Abdel-Hafiz L 5 , Huston JP 5 , Smaga I 6 , Frankowska M 6 , Filip M 6 , Lourdusamy A 7 , Kirchner P 8 , Ekici AB 8 , Marx LM 1 , Suresh NP 1 , Frischknecht R 9 , Fejtova A 1 , Saied EM 10 , Arenz C 10 , Bozec A 11 , Wank I 12 , Kreitz S 12 , Hess A 12 , Bäuerle T 13 , Ledesma MD 14 , Mitroi DN 14 , Miranda AM 15 , Oliveira TG 15 , Lenz B 1 , Schumann G 1 , Kornhuber J 1 , Müller CP 1

Affiliations 

  • 1 Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 6, Erlangen 91054, Germany
  • 2 The Centre for Population Neuroscience and Stratified Medicine (PONS), ISTBI, Fudan University, Shanghai 200433, China
  • 3 Department for Anesthesiology and Intensive Care, Faculty of Medicine, University of Leipzig, Leipzig 04103, Germany
  • 4 School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland
  • 5 Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf 40225, Germany
  • 6 Department of Drug Addiction Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, Kraków 31-343, Poland
  • 7 Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
  • 8 Institute of Human Genetics, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen 91054, Germany
  • 9 Department of Biology, Animal Physiology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91058, Germany
  • 10 Institute for Chemistry, Humboldt University, Berlin 12489, Germany
  • 11 Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen 91054, Germany
  • 12 Department of Experimental and Clinical Pharmacology and Toxicology, Emil Fischer Center, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), Erlangen, Germany
  • 13 Preclinical Imaging Platform Erlangen, Institute of Radiology, University Hospital Erlangen, Erlangen 91054, Germany
  • 14 Centro Biologia Molecular Severo Ochoa (CSIC-UAM), Madrid 28040, Spain
  • 15 School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Campus Gualtar, Braga 4710-057, Portugal
Cereb Cortex, 2023 Jan 05;33(3):844-864.
PMID: 35296883 DOI: 10.1093/cercor/bhac106

Abstract

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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