Reporting in Nature Medicine, Gulbins et al. show that therapeutic concentrations of the tricyclic antidepressant amitriptyline or the selective serotonin reuptake inhibitor (SSRI) fluoxetine reduced the activity of acid sphingomyelinase (ASM) — a ubiquitously expressed enzyme that releases ceramide from sphingomyelin — in cultured neurons and in mouse hippocampi. Mice expressing high concentrations of ceramide in the hippocampus showed lower rates of neurogenesis, neuronal maturation and survival, as well as depression-like behaviour even in the absence of stress. Antidepressants improved the depression-like behaviour of mice while also increasing neuronal proliferation, maturation and survival in the hippocampus via inhibition of ASM and a reduction in ceramide levels. Together, these findings suggest that specifically reducing ceramide levels — for instance, by targeting ASM — could be a useful strategy for developing new antidepressants.
In a study in the Journal of Neuroscience, Horton et al. show that decynium-22 (D-22), a synthetic blocker of organic cation transporters (OCTs), greatly enhanced the antidepressant-like effect of the SSRI fluvoxamine in mice. SSRIs are thought to exert their effects by increasing the extracellular levels of serotonin. However, the presence of low-affinity, high-capacity serotonin transporters that function as secondary serotonin reuptake sites may contribute to the clearance of serotonin from the extracellular fluid and thus could explain the limited therapeutic efficacy of SSRIs. Indeed, the authors show that these transporters are sensitive to D-22 and that the fluvoxamine-induced inhibition of serotonin clearance in the hippocampus is enhanced following intraperitoneal injection of D-22. Interestingly, the antidepressant-like effect of D-22 was attenuated in Oct3-knockout mice despite still inhibiting serotonin clearance in the hippocampus, which suggests that, in addition to OCT3, other low-affinity, high-capacity D-22-sensitive serotonin transporters could represent novel targets for antidepressant drugs.
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