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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.<\/jats:p>","DOI":"10.1093\/cercor\/bhac106","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T20:13:17Z","timestamp":1645733597000},"page":"844-864","source":"Crossref","is-referenced-by-count":16,"title":["Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males"],"prefix":"10.1093","volume":"33","author":[{"given":"Liubov S","family":"Kalinichenko","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg , Schwabachanlage 6, Erlangen 91054, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christiane","family":"M\u00fchle","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg , Schwabachanlage 6, Erlangen 91054, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5399-2953","authenticated-orcid":false,"given":"Tianye","family":"Jia","sequence":"additional","affiliation":[{"name":"The Centre for Population Neuroscience and Stratified Medicine (PONS), ISTBI, Fudan University , Shanghai 200433, China"},{"name":"PONS Centre and SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London , London SE5 8AB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felix","family":"Anderheiden","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg , Schwabachanlage 6, Erlangen 91054, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Datz","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg , Schwabachanlage 6, Erlangen 91054, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna-Lisa","family":"Eberle","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg , Schwabachanlage 6, Erlangen 91054, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Volker","family":"Eulenburg","sequence":"additional","affiliation":[{"name":"Department for Anesthesiology and Intensive Care , Faculty of Medicine, , Leipzig 04103, Germany"},{"name":"University of Leipzig , Faculty of Medicine, , Leipzig 04103, 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f\u00fcr Immuntherapie (DZI) , Erlangen 91054, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Wank","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology and Toxicology, Emil Fischer Center, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU) , Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silke","family":"Kreitz","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology and Toxicology, Emil Fischer Center, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU) , Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Hess","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology and Toxicology, Emil Fischer Center, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU) , Erlangen, 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