Department of Psychiatry & Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.
Center for Brain Research in Mood Disorders, Washington University School of Medicine, St. Louis, MO, USA.
Transl Psychiatry. 2024 Nov 21;14(1):474. doi: 10.1038/s41398-024-03185-3.
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.
除了调节血清素转运，选择性血清素再摄取抑制剂（SSRIs）还有其他多种可能导致临床效果的机制，其中一些作用促使 SSRIs 被重新用于非精神疾病的适应证。在最近一项对 SSRIs 氟伏沙明、氟西汀和舍曲林的研究中，我们发现与另外两种 SSRIs 不同，舍曲林通过对 sigma 1 受体（S1Rs）的反向激动作用，以低微摩尔浓度急性抑制 LTP。在本研究中，我们研究了导致舍曲林调节大鼠海马切片 LTP 的机制。我们发现，舍曲林通过对包含 GluN2B 亚基的 N-甲基-D-天冬氨酸受体（NMDARs）的作用，部分抑制由 NMDARs 介导的突触反应。选择性 S1R 拮抗剂（NE-100），而非 S1R 激动剂（PRE-084）阻断了对 NMDARs 的作用，尽管这两种 S1R 配体先前均被证明可阻止 LTP 抑制。然而，NE-100 和 PRE-084 均阻止了舍曲林对单次试验学习的不良影响。由于 S1Rs 在调节内质网应激中起着重要作用，我们研究了细胞应激抑制剂是否会改变舍曲林的作用。我们发现，两种应激抑制剂 ISRIB 和槲皮素，以及内源性神经甾体的合成抑制剂，均可阻止 LTP 抑制，而神经甾体是细胞应激的内稳态调节剂。这些研究突出了舍曲林、S1Rs 和神经甾体对海马功能的复杂影响，并对理解治疗和药物不良反应具有重要意义。
