Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208.
Department of Pharmacology, Physiology, and Neuroscience, School of Medicine Columbia, University of South Carolina, Columbia, South Carolina 29209.
J Neurosci. 2021 Jul 28;41(30):6564-6577. doi: 10.1523/JNEUROSCI.2618-20.2021. Epub 2021 Jun 3.
Commonly prescribed selective serotonin reuptake inhibitors (SSRIs) inhibit the serotonin transporter to correct a presumed deficit in extracellular serotonin signaling during depression. These agents bring clinical relief to many who take them; however, a significant and growing number of individuals are resistant to SSRIs. There is emerging evidence that inflammation plays a significant role in the clinical variability of SSRIs, though how SSRIs and inflammation intersect with synaptic serotonin modulation remains unknown. In this work, we use fast serotonin measurement tools to investigate the nexus between serotonin, inflammation, and SSRIs. Upon acute systemic lipopolysaccharide (LPS) administration in male and female mice, we find robust decreases in extracellular serotonin in the mouse hippocampus. We show that these decreased serotonin levels are supported by increased histamine activity (because of inflammation), acting on inhibitory histamine H3 heteroreceptors on serotonin terminals. Importantly, under LPS-induced histamine increase, the ability of escitalopram to augment extracellular serotonin is impaired because of an off-target action of escitalopram to inhibit histamine reuptake. Finally, we show that a functional decrease in histamine synthesis boosts the ability of escitalopram to increase extracellular serotonin levels following LPS. This work reveals a profound effect of inflammation on brain chemistry, specifically the rapidity of inflammation-induced decreased extracellular serotonin, and points the spotlight at a potentially critical player in the pathology of depression, histamine. The serotonin/histamine homeostasis thus, may be a crucial new avenue in improving serotonin-based treatments for depression. Acute LPS-induced inflammation (1) increases CNS histamine, (2) decreases CNS serotonin (via inhibitory histamine receptors), and (3) prevents a selective serotonin reuptake inhibitor (SSRI) from effectively increasing extracellular serotonin. A targeted depletion of histamine recovers SSRI-induced increases in extracellular hippocampal serotonin.
常用的选择性 5-羟色胺再摄取抑制剂（SSRIs）抑制 5-羟色胺转运体，以纠正抑郁时细胞外 5-羟色胺信号传递的假定不足。这些药物为许多服用者带来了临床缓解；然而，越来越多的人对 SSRIs 产生了抗药性。有新的证据表明，炎症在 SSRIs 的临床变异性中起着重要作用，尽管 SSRIs 和炎症如何与突触 5-羟色胺调节相互作用仍然未知。在这项工作中，我们使用快速 5-羟色胺测量工具来研究 5-羟色胺、炎症和 SSRIs 之间的关系。在雄性和雌性小鼠急性全身给予脂多糖（LPS）后，我们发现小鼠海马体细胞外 5-羟色胺水平显著下降。我们表明，这些 5-羟色胺水平的降低是由炎症引起的组胺活性增加（由于炎症）支持的，作用于 5-羟色胺末端的抑制性组胺 H3 变构受体。重要的是，在 LPS 诱导的组胺增加下，由于依他普仑对组胺再摄取的非靶向作用，依他普仑增强细胞外 5-羟色胺的能力受损。最后，我们表明，组胺合成的功能降低会增强依他普仑在 LPS 后增加细胞外 5-羟色胺水平的能力。这项工作揭示了炎症对大脑化学物质的深远影响，特别是炎症诱导的细胞外 5-羟色胺快速下降，并凸显了组胺在抑郁症病理中的一个潜在关键因素。因此，5-羟色胺/组胺平衡可能是改善基于 5-羟色胺的抑郁症治疗的一个重要新途径。急性 LPS 诱导的炎症 (1) 增加中枢神经系统组胺，(2) 降低中枢神经系统 5-羟色胺（通过抑制性组胺受体），(3) 阻止选择性 5-羟色胺再摄取抑制剂（SSRI）有效地增加细胞外 5-羟色胺。组胺的靶向耗竭恢复了 SSRI 诱导的海马细胞外 5-羟色胺增加。
