Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids
Abstract In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other mechanisms that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. In a recent study of the SSRIs...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-11-01
|
| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-024-03185-3 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846158201998802944 |
|---|---|
| author | Yukitoshi Izumi Angela M. Reiersen Eric J. Lenze Steven J. Mennerick Charles F. Zorumski |
| author_facet | Yukitoshi Izumi Angela M. Reiersen Eric J. Lenze Steven J. Mennerick Charles F. Zorumski |
| author_sort | Yukitoshi Izumi |
| collection | DOAJ |
| description | Abstract In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other mechanisms that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. In a recent study of the SSRIs fluvoxamine, fluoxetine and sertraline we found that, unlike the other two SSRIs, sertraline acutely inhibited LTP at a low micromolar concentration through inverse agonism of sigma 1 receptors (S1Rs). In the present studies, we pursued mechanisms contributing to sertraline modulation of LTP in rat hippocampal slices. We found that sertraline partially inhibits synaptic responses mediated by N-methyl-D-aspartate receptors (NMDARs) via effects on NMDARs that contain GluN2B subunits. A selective S1R antagonist (NE-100), but not an S1R agonist (PRE-084) blocked effects on NMDARs, even though both S1R ligands were previously shown to prevent LTP inhibition. Both NE-100 and PRE-084, however, prevented adverse effects of sertraline on one-trial learning. Because of the important role that S1Rs play in modulating endoplasmic reticulum stress, we examined whether inhibitors of cellular stress alter effects of sertraline. We found that two stress inhibitors, ISRIB and quercetin, prevented LTP inhibition, as did inhibitors of the synthesis of endogenous neurosteroids, which are homeostatic regulators of cellular stress. These studies highlight complex effects of sertraline, S1Rs and neurosteroids on hippocampal function and have relevance for understanding therapeutic and adverse drug actions. |
| format | Article |
| id | doaj-art-d4224406a23c4044a195a81fbf174899 |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-d4224406a23c4044a195a81fbf1748992024-11-24T12:43:55ZengNature Publishing GroupTranslational Psychiatry2158-31882024-11-0114111110.1038/s41398-024-03185-3Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroidsYukitoshi Izumi0Angela M. Reiersen1Eric J. Lenze2Steven J. Mennerick3Charles F. Zorumski4Department of Psychiatry & Taylor Family Institute for Innovative Psychiatric Research, Washington University School of MedicineDepartment of Psychiatry & Taylor Family Institute for Innovative Psychiatric Research, Washington University School of MedicineDepartment of Psychiatry & Taylor Family Institute for Innovative Psychiatric Research, Washington University School of MedicineDepartment of Psychiatry & Taylor Family Institute for Innovative Psychiatric Research, Washington University School of MedicineDepartment of Psychiatry & Taylor Family Institute for Innovative Psychiatric Research, Washington University School of MedicineAbstract In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other mechanisms that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. In a recent study of the SSRIs fluvoxamine, fluoxetine and sertraline we found that, unlike the other two SSRIs, sertraline acutely inhibited LTP at a low micromolar concentration through inverse agonism of sigma 1 receptors (S1Rs). In the present studies, we pursued mechanisms contributing to sertraline modulation of LTP in rat hippocampal slices. We found that sertraline partially inhibits synaptic responses mediated by N-methyl-D-aspartate receptors (NMDARs) via effects on NMDARs that contain GluN2B subunits. A selective S1R antagonist (NE-100), but not an S1R agonist (PRE-084) blocked effects on NMDARs, even though both S1R ligands were previously shown to prevent LTP inhibition. Both NE-100 and PRE-084, however, prevented adverse effects of sertraline on one-trial learning. Because of the important role that S1Rs play in modulating endoplasmic reticulum stress, we examined whether inhibitors of cellular stress alter effects of sertraline. We found that two stress inhibitors, ISRIB and quercetin, prevented LTP inhibition, as did inhibitors of the synthesis of endogenous neurosteroids, which are homeostatic regulators of cellular stress. These studies highlight complex effects of sertraline, S1Rs and neurosteroids on hippocampal function and have relevance for understanding therapeutic and adverse drug actions.https://doi.org/10.1038/s41398-024-03185-3 |
| spellingShingle | Yukitoshi Izumi Angela M. Reiersen Eric J. Lenze Steven J. Mennerick Charles F. Zorumski Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids Translational Psychiatry |
| title | Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids |
| title_full | Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids |
| title_fullStr | Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids |
| title_full_unstemmed | Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids |
| title_short | Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids |
| title_sort | sertraline modulates hippocampal plasticity via sigma 1 receptors cellular stress and neurosteroids |
| url | https://doi.org/10.1038/s41398-024-03185-3 |
| work_keys_str_mv | AT yukitoshiizumi sertralinemodulateshippocampalplasticityviasigma1receptorscellularstressandneurosteroids AT angelamreiersen sertralinemodulateshippocampalplasticityviasigma1receptorscellularstressandneurosteroids AT ericjlenze sertralinemodulateshippocampalplasticityviasigma1receptorscellularstressandneurosteroids AT stevenjmennerick sertralinemodulateshippocampalplasticityviasigma1receptorscellularstressandneurosteroids AT charlesfzorumski sertralinemodulateshippocampalplasticityviasigma1receptorscellularstressandneurosteroids |