title: Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs.
abstract: Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany. erich.gulbins@uni-due.de
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
authors.forename: Monica
authors.initials: M
authors.lastname: Palmada
authors.forename: Martin
authors.initials: M
authors.lastname: Reichel
authors.forename: Anja
authors.initials: A
authors.lastname: Lüth
authors.forename: Christoph
authors.initials: C
authors.lastname: Böhmer
authors.forename: Davide
authors.initials: D
authors.lastname: Amato
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
authors.forename: Carsten H
authors.initials: CH
authors.lastname: Tischbirek
authors.forename: Teja W
authors.initials: TW
authors.lastname: Groemer
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Tabatabai
authors.forename: Katrin A
authors.initials: KA
authors.lastname: Becker
authors.forename: Philipp
authors.initials: P
authors.lastname: Tripal
authors.forename: Sven
authors.initials: S
authors.lastname: Staedtler
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Ackermann
authors.forename: Johannes
authors.initials: J
authors.lastname: van Brederode
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Undine E
authors.initials: UE
authors.lastname: Lang
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.forename: Heike
authors.initials: H
authors.lastname: Grassmé
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000928:Antidepressive Agents / Q000494:pharmacology*; D017173:Caenorhabditis elegans; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism / Q000502:physiology*; D003865:Major Depressive Disorder / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D000928:Antidepressive Agents; D002518:Ceramides; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase