Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 19 (7), 934-8

Acid Sphingomyelinase-Ceramide System Mediates Effects of Antidepressant Drugs

Affiliations

Acid Sphingomyelinase-Ceramide System Mediates Effects of Antidepressant Drugs

Erich Gulbins et al. Nat Med.

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.

Comment in

Similar articles

See all similar articles

Cited by 60 PubMed Central articles

See all "Cited by" articles

References

    1. J Med Chem. 2008 Jan 24;51(2):219-37 - PubMed
    1. J Biol Chem. 1991 Jan 5;266(1):484-9 - PubMed
    1. Brain Res. 2004 Aug 20;1018(1):73-7 - PubMed
    1. Cell Death Differ. 2001 Jan;8(1):100-3 - PubMed
    1. Dialogues Clin Neurosci. 2005;7(3):231-47 - PubMed

Publication types

MeSH terms

Feedback