Melatonin Acts as an Antidepressant by Inhibition of the Acid Sphingomyelinase/Ceramide System.

Background: Melatonin has been shown to have antidepressive effects. We tested whether melatonin inhibits the acid sphingomyelinase/ceramide system and mediates its antidepressive effects via inhibition of the acid sphingomyelinase and a reduction of ceramide in the hippocampus. Antidepressants such as amitriptyline and fluoxetine were previously shown to inhibit the acid sphingomyelinase/ceramide system, which mediates neurogenesis and behavioral changes induced by these drugs. Methods: The effect of melatonin on the activity of the acid sphingomyelinase prior to and after treatment with melatonin was determined in cultured neurons and in vivo in the hippocampus of mice by measuring the consumption of [14C] sphingomyelin. Ceramide was measured by DAG kinase assay and fluorescence microscopy of the hippocampus and of cultured neurons. Neurogenesis in the hippocampus was analyzed by in vivo labeling with bromodeoxyuridine. Behavior was assessed in standardized tests. Results: Melatonin treatment inhibited acid sphingomyelinase in vitro in cultured pheochromocytoma cells and in vivo in the hippocampus, which resulted in a reduction of ceramide in vitro and in vivo. The inhibition of the acid sphingomyelinase/ceramide system translated into increased neurogenesis in glucocorticosterone-stressed mice after treatment with melatonin, an effect that is abrogated in acid sphingomyelinase-deficient mice. Likewise, melatonin improved the depressive behavior of stressed mice, a therapeutic effect that was again absent in acid sphingomyelinase-deficient animals. Conclusion: These data indicate that the antidepressive effects of melatonin as well as the induction of neurogenesis triggered by this drug are mediated by an inhibition of the acid sphingomyelinase/ceramide system. This is the first study to identify melatonin as an inhibitor of the acid sphingomyelinase.